Laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS) patients with a high disability status

ABSTRACT

This invention provides a method for treating or for reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to treat the patient or to reduce ambulatory deterioration. This invention further provides pharmaceutical compositions and packages comprising an effective amount of laquinimod for treating a human patient diagnosed to be afflicted with RRMS and having a high baseline disability score according to the EDSS.

This application is a continuation of U.S. Ser. No. 14/698,319, filedApr. 28, 2015, which claims benefit of U.S. Provisional Application No.61/985,886, filed Apr. 29, 2014, U.S. Provisional Application No.62/046,561, filed Sep. 5, 2014, U.S. Provisional Application No.62/119,506, filed Feb. 23, 2015, and U.S. Provisional Application No.62/139,978, filed Mar. 30, 2015, the entire content of each of which arehereby incorporated by reference herein.

Throughout this application, various publications are referred to byfirst author and year of publication. Full citations for thesepublications are presented in a References section immediately beforethe claims. Disclosures of the publications cited in the Referencessection in their entireties are hereby incorporated by reference intothis application in order to more fully describe the state of the art asof the date of the invention described herein.

BACKGROUND

Multiple Sclerosis (MS) is a neurological disease affecting more than 1million people worldwide. It is the most common cause of neurologicaldisability in young and middle-aged adults and has a major physical,psychological, social and financial impact on subjects and theirfamilies, friends and bodies responsible for health care. (EMEAGuideline, 2006) It is generally assumed that MS is mediated by somekind of autoimmune process possibly triggered by infection andsuperimposed upon a genetic predisposition. It is a chronic inflammatorycondition that damages the myelin of the Central Nervous System (CNS).The pathogenesis of MS is characterized by the infiltration ofautoreactive T-cells from the circulation directed against myelinantigens into the CNS. (Bjartmar, 2002) In addition to the inflammatoryphase in MS, axonal loss occurs early in the course of the disease andcan be extensive over time, leading to the subsequent development ofprogressive, permanent, neurologic impairment and, frequently, severedisability. (Neuhaus, 2003) Symptoms associated with the disease includefatigue, spasticity, ataxia, weakness, bladder and bowel disturbances,sexual dysfunction, pain, tremor, paroxysmal manifestations, visualimpairment, psychological problems and cognitive dysfunction. (EMEAGuideline, 2006)

Various MS disease stages and/or types are described in MultipleSclerosis Therapeutics. (Duntiz, 1999) Among them, relapsing-remittingMS (RRMS) is the most common form at the time of initial diagnosis. Manysubjects with RRMS have an initial relapsing-remitting course for 5-15years, which then advances into the secondary progressive MS (SPMS)disease course. Relapses result from inflammation and demyelination,whereas restoration of nerve conduction and remission is accompanied byresolution of inflammation, redistribution of sodium channels ondemyelinated axons and remyelination. (Neuhaus, 2003; Noseworthy, 2000)

In April 2001, an international panel in association with the NationalMS Society of America recommended diagnostic criteria for MS. Thesecriteria became known as the McDonald Criteria, which make use of MRItechniques and are intended to replace the Poser Criteria and the olderSchumacher Criteria. (McDonald, 2001) The McDonald Criteria was revisedin March 2005 by an international panel. (Polman, 2005)

Intervention with disease-modifying therapy at relapsing stages of MS issuggested to reduce and/or prevent accumulating neurodegeneration.(Hohlfeld, 2000; De Stefano, 1999) Disease-modifying medicationscurrently approved for use in relapsing MS (RMS; which includes RRMS andSPMS; The Disease Modifying Drug Brochure, 2006) include interferon beta1-a (Avonex® and Rebif®), interferon beta 1-b (Betaseron®), glatirameracetate) (Copaxone®), mitoxantrone (Novantrone®) and natalizumab)(Tysabri®). Most of them are believed to act as immunomodulators.Mitoxantrone and natalizumab are believed to act as immunesuppressants.However, the mechanisms of action of each have been only partlyelucidated. Immunosuppressants or cytotoxic agents are sometimes usedafter failure of conventional therapies. However, the relationshipbetween changes of the immune response induced by these agents and theclinical efficacy in MS is far from settled. (EMEA Guideline, 2006)Other therapeutic approaches include symptomatic treatment which refersto all therapies applied to improve the symptoms caused by the disease(EMEA Guideline, 2006) and treatment of acute relapses withcorticosteroids. While steroids do not affect the course of MS overtime, they can reduce the duration and severity of attacks in somesubjects.

Laquinimod sodium is a novel synthetic compound with high oralbioavailability, which has been suggested as an oral formulation for thetreatment of MS. (Polman, 2005; Sandberg-Wollheim, 2005) Studies haveshown laquinimod to reduce development of active MRI lesions inrelapsing MS. (Polman, 2005) However, the clinical significance of MRIbrain lesion reduction alone is still unsettled. Although MRI lesionsare used as the primary outcome measure in some studies, others havesuggested that correlation between MRI abnormalities and clinicaldisease activity in RRMS patients is weak and that such measurementshould be used as secondary outcomes rather than as surrogate markers ofclinical responses. (Rudick, 1999; Miki, 1999; Barkhof, 1999) Further,according to pharmaceutical regulatory bodies such as the EuropeanMedicines Agency (EMEA), the correlation between MRI results andclinical outcomes has not been proved strong enough so as to accept MRIresults as validated surrogate endpoint in pivotal studies. Therefore,according to the EMEA, the relevant efficacy parameter for clinicaltrials is the accumulation of disability and relapse rate (for RRMS).(EMEA Guideline, 2006) Thus, relapse rate and disability progression arethe currently accepted indicators of effectiveness of a RRMS treatment.

The EMEA MS clinical trials guideline further states that the annualrelapse rate in RRMS is usually low and that, generally, disabilityprogression takes years. Consequently, confirmatory studies withproducts intended to modify the course of the disease should be largescale and long enough to have a substantial proportion of patientssuffering relapses or showing progression of disability. Two years isconsidered the minimum duration to demonstrate efficacy. (EMEAGuideline, 2006)

SUMMARY OF THE INVENTION

The subject invention provides a method of treating a human patientdiagnosed to be afflicted with relapsing-remitting multiple sclerosis(RRMS) and having a high baseline disability score according to theKurtzke Expanded Disability Status Scale (EDSS), comprising periodicallyadministering to only the patient diagnosed with RRMS and having a highbaseline disability score an amount of laquinimod effective to treat thepatient.

The subject invention also provides a method of treating a human patientafflicted with relapsing-remitting multiple sclerosis (RRMS), comprisinga) diagnosing the patient as having a high baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS), and b)administering to the patient an amount of laquinimod effective to treatthe patient only if the patient has been diagnosed as having a highbaseline disability score.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with relapsing-remitting multiple sclerosis(RRMS) and having a baseline disability score according to the KurtzkeExpanded Disability Status Scale (EDSS) of greater than 3.0, comprisingperiodically administering to only the patient diagnosed with RRMS andhaving a EDSS score of greater than 3.0 an amount of laquinimodeffective to treat the patient.

The subject invention also provides a method of treating a human patientafflicted with relapsing-remitting multiple sclerosis (RRMS), comprisinga) diagnosing the patient as having a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3.0, and b) administering to the patient an amount oflaquinimod effective to treat the patient only if the patient has beendiagnosed as having an EDSS score of greater than 3.0.

The subject invention also provides a method of reducing ambulatorydeterioration in a human patient diagnosed to be afflicted withrelapsing-remitting multiple sclerosis (RRMS) and having a high baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS), comprising periodically administering to only the patientdiagnosed with RRMS and having a high baseline disability score anamount of laquinimod effective to reduce ambulatory deterioration.

The subject invention also provides a method of reducing ambulatorydeterioration in a human patient diagnosed to be afflicted withrelapsing-remitting multiple sclerosis (RRMS) and having a baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS) of greater than 3.0, comprising periodically administeringto only the patient diagnosed with RRMS and having a baseline EDSS ofgreater than 3.0 an amount of laquinimod effective to reduce ambulatorydeterioration.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS).

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having a high baseline disability score accordingto the Kurtzke Expanded Disability Status Scale (EDSS).

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with relapsing-remittingmultiple sclerosis (RRMS) and having a high baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS).

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS), which comprises: a) one or more unitdoses, each such unit dose comprising an amount of laquinimod thereof,wherein the amount of said laquinimod in said unit dose is effective,upon administration to said patient, to treat the patient, and b) afinished pharmaceutical container therefor, said container containingsaid unit dose or unit doses, said container further containing orcomprising labeling directing the use of said package in the treatmentof said patient.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga baseline disability score according to the Kurtzke Expanded DisabilityStatus Scale (EDSS) of greater than 3.0.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having a baseline disability score according to theKurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with relapsing-remittingmultiple sclerosis (RRMS) and having a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3.0.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga baseline disability score according to the Kurtzke Expanded DisabilityStatus Scale (EDSS) of greater than 3.0, which comprises: a) one or moreunit doses, each such unit dose comprising an amount of laquinimodthereof, wherein the amount of said laquinimod in said unit dose iseffective, upon administration to said patient, to treat the patient,and b) a finished pharmaceutical container therefor, said containercontaining said unit dose or unit doses, said container furthercontaining or comprising labeling directing the use of said package inthe treatment of said patient.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with RRMS and having impaired mobility,comprising periodically administering to only the patient diagnosed withRRMS and having impaired mobility an amount of laquinimod effective totreat the patient.

The subject invention further provides a method of treating a humanpatient afflicted with RRMS, comprising a) diagnosing the patient ashaving mobility impairment as assessed by the patient's Timed-25 footwalk test core, and b) administering to the patient an amount oflaquinimod effective to treat the patient only if the patient has beendiagnosed as having a mobility impairment.

The subject invention further provides a method of reducing mobilitydeterioration in a human patient diagnosed to be afflicted with RMS andhaving impaired mobility, comprising periodically administering to onlythe patient diagnosed with RRMS and having impaired mobility an amountof laquinimod effective to reduce mobility deterioration.

The subject invention further provides laquinimod for the manufacture ofa medicament for use in treating only a human patient diagnosed to beafflicted with RRMS and having impaired mobility.

The subject invention further provides a pharmaceutical compositioncomprising an effective amount of laquinimod for use in treating only ahuman patient diagnosed to be afflicted with RRMS and having impairedmobility.

The subject invention further provides a package comprising a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with RRMS and having impairedmobility.

The subject invention further provides a therapeutic package fordispensing to, or for use in dispensing to, only a human patientdiagnosed to be afflicted with RRMS and having impaired mobility, whichcomprises: a) one or more unit doses, each such unit dose comprising anamount of laquinimod thereof, wherein the amount of said laquinimod insaid unit dose is effective, upon administration to said patient, totreat the patient, and b) a finished pharmaceutical container therefor,said container containing said unit dose or unit doses, said containerfurther containing or comprising labeling directing the use of saidpackage in the treatment of said patient.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with RRMS and having worsening MS, comprisingperiodically administering to only the patient diagnosed with RRMS andhaving worsening MS an amount of laquinimod effective to treat thepatient.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havingworsening MS.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having worsening MS.

The subject invention also provides a package comprising a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with RRMS and having worseningMS.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with RRMS and having worsening MS, which comprises: a) one ormore unit doses, each such unit dose comprising an amount of laquinimodthereof, wherein the amount of said laquinimod in said unit dose iseffective, upon administration to said patient, to treat the patient,and b) a finished pharmaceutical container therefor, said containercontaining said unit dose or unit doses, said container furthercontaining or comprising labeling directing the use of said package inthe treatment of said patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Example 3: Time 25-Foot Walk (T25FW) Results (Mean Change fromBaseline to 24 Months) in the EDSS≦3 Patient group versus the EDSS>3Patient group.

FIG. 2: Example 3: Time 25-Foot Walk (T25FW) Results (Mean Change fromBaseline to 24 Month) by Treatment in Patients with EDSS>3 whoexperienced CDP.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a method of treating a human patientdiagnosed to be afflicted with relapsing-remitting multiple sclerosis(RRMS) and having a high baseline disability score according to theKurtzke Expanded Disability Status Scale (EDSS), comprising periodicallyadministering to only the patient diagnosed with RRMS and having a highbaseline disability score an amount of laquinimod effective to treat thepatient.

The subject invention also provides a method of treating a human patientafflicted with relapsing-remitting multiple sclerosis (RRMS), comprisinga) diagnosing the patient as having a high baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS), and b)administering to the patient an amount of laquinimod effective to treatthe patient only if the patient has been diagnosed as having a highbaseline disability score.

In one embodiment, the high baseline disability score is a baseline EDSSscore of greater than 3. In another embodiment, the high baselinedisability score is a baseline EDSS score of greater than 3.5. Inanother embodiment, the high baseline disability score is a baselineEDSS score of greater than 4.0. In another embodiment, the high baselinedisability score is a baseline EDSS score of greater than 4.5. Inanother embodiment, the high baseline disability score is a baselineEDSS score of greater than 5.0. In another embodiment, the high baselinedisability score is a baseline EDSS score of greater than 5.5.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with relapsing-remitting multiple sclerosis(RRMS) and having a baseline disability score according to the KurtzkeExpanded Disability Status Scale (EDSS) of greater than 3.0, comprisingperiodically administering to only the patient diagnosed with RRMS andhaving a EDSS score of greater than 3.0 an amount of laquinimodeffective to treat the patient.

The subject invention also provides a method of treating a human patientafflicted with relapsing-remitting multiple sclerosis (RRMS), comprisinga) diagnosing the patient as having a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3.0, and b) administering to the patient an amount oflaquinimod effective to treat the patient only if the patient has beendiagnosed as having an EDSS score of greater than 3.0.

In one embodiment, the amount of laquinimod is effective to reduce thepatient's relapse rate. In another embodiment, the amount of laquinimodis effective to reduce the patient's accumulation of physicaldisability.

In an embodiment, the accumulation of physical disability is assessed bythe patient's Multiple Sclerosis Functional Composite (MSFC) score. Inanother embodiment, the amount of laquinimod is effective to reducedeterioration of the patient's ambulation. In another embodiment,ambulation is assessed by the patient's Timed-25 foot walk test score.In another embodiment, after 24 months of periodic administration oflaquinimod, the patient's accumulation of physical disability is reducedas compared to a patient not receiving periodic administration oflaquinimod.

In an embodiment, the accumulation of physical disability is assessed bythe time to confirmed disease progression (CDP) as measured by EDSSscore. In another embodiment, the patient has a baseline EDSS score of3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 3.5, and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 4.0, and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 4.5, and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 5.0, and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 5.5, and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of 5.5 orgreater and CDP is a 0.5 point increase of the baseline EDSS score.

In one embodiment, CDP is sustained for at least 3 months. In anotherembodiment, CDP is sustained for at least 6 months.

The subject invention also provides a method of reducing ambulatorydeterioration in a human patient diagnosed to be afflicted withrelapsing-remitting multiple sclerosis (RRMS) and having a high baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS), comprising periodically administering to only the patientdiagnosed with RRMS and having a high baseline disability score anamount of laquinimod effective to reduce ambulatory deterioration. In anembodiment, the high baseline disability score is a baseline EDSS scoreof greater than 3.

The subject invention also provides a method of reducing ambulatorydeterioration in a human patient diagnosed to be afflicted withrelapsing-remitting multiple sclerosis (RRMS) and having a baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS) of greater than 3.0, comprising periodically administeringto only the patient diagnosed with RRMS and having a baseline EDSS ofgreater than 3.0 an amount of laquinimod effective to reduce ambulatorydeterioration.

In one embodiment, ambulation is assessed by the patient's Timed-25 footwalk test score. In another embodiment, after 24 months of periodicadministration of laquinimod, deterioration of the patient's ambulationis reduced as compared to a patient not receiving periodicadministration of laquinimod.

In an embodiment, the patient has been diagnosed with a baseline EDSSscore of greater than 3.5. In another embodiment, the patient has beendiagnosed with a baseline EDSS score of greater than 4.0. In anotherembodiment, the patient has been diagnosed with a baseline EDSS score ofgreater than 4.5. In another embodiment, the patient has been diagnosedwith a baseline EDSS score of greater than 5.0. In another embodiment,the patient has been diagnosed with a baseline EDSS score of greaterthan 5.5. In yet another embodiment, the patient has been diagnosed witha baseline EDSS score of 3.5-5.5.

In one embodiment, the patient is naïve to an RRMS treatment. In anotherembodiment, the patient is naïve to any RRMS treatment. In anotherembodiment, the patient is naïve to laquinimod treatment. In anotherembodiment, the patient is naïve to 0.3 mg/day laquinimod treatment. Inanother embodiment, the patient is naïve to 0.6 mg/day laquinimodtreatment. In another embodiment, the patient is naïve to 1.2 mg/daylaquinimod treatment.

In one embodiment, laquinimod is laquinimod sodium. In anotherembodiment, laquinimod is administered orally. In another embodiment,laquinimod is administered daily.

In one embodiment, laquinimod is administered at a daily dose of 0.1-2.5mg laquinimod. In another embodiment of the present invention, theamount laquinimod administered is 0.25 mg/day. In another embodiment,the amount laquinimod administered is 0.3 mg/day. In another embodiment,the amount laquinimod administered is 0.5 mg/day. In another embodiment,the amount laquinimod administered is 0.6 mg/day. In another embodiment,the amount laquinimod administered is 0.9 mg/day. In another embodiment,the amount laquinimod administered is 1.0 mg/day. In another embodiment,the amount laquinimod administered is 1.2 mg/day. In another embodiment,the amount laquinimod administered is 1.5 mg/day. In another embodiment,the amount laquinimod administered is 1.8 mg/day. In another embodiment,the amount laquinimod administered is 2.0 mg/day. In another embodiment,the amount laquinimod administered is 2.5 mg/day. In yet anotherembodiment, the amount of laquinimod administered is about the amountsdisclosed above.

In one embodiment, the periodic administration is for a period ofgreater than 24 weeks. In another embodiment, laquinimod is administeredas monotherapy for RRMS. In another embodiment, laquinimod isadministered as adjunct therapy with an other RRMS treatment. In anotherembodiment, the other RRMS treatment is administration of interferonbeta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone ornatalizumab.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS). In an embodiment, the high baselinedisability score is a baseline EDSS score of greater than 3.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having a high baseline disability score accordingto the Kurtzke Expanded Disability Status Scale (EDSS). In anembodiment, the high baseline disability score is a baseline EDSS scoreof greater than 3.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with relapsing-remittingmultiple sclerosis (RRMS) and having a high baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS). In anembodiment, the high baseline disability score is a baseline EDSS scoreof greater than 3.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS), which comprises: a) one or more unitdoses, each such unit dose comprising an amount of laquinimod thereof,wherein the amount of said laquinimod in said unit dose is effective,upon administration to said patient, to treat the patient, and b) afinished pharmaceutical container therefor, said container containingsaid unit dose or unit doses, said container further containing orcomprising labeling directing the use of said package in the treatmentof said patient. In an embodiment, the high baseline disability score isa baseline EDSS score of greater than 3.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga baseline disability score according to the Kurtzke Expanded DisabilityStatus Scale (EDSS) of greater than 3.0.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having a baseline disability score according to theKurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with relapsing-remittingmultiple sclerosis (RRMS) and having a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3.0.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga baseline disability score according to the Kurtzke Expanded DisabilityStatus Scale (EDSS) of greater than 3.0, which comprises: a) one or moreunit doses, each such unit dose comprising an amount of laquinimodthereof, wherein the amount of said laquinimod in said unit dose iseffective, upon administration to said patient, to treat the patient,and b) a finished pharmaceutical container therefor, said containercontaining said unit dose or unit doses, said container furthercontaining or comprising labeling directing the use of said package inthe treatment of said patient.

The subject invention also provides laquinimod for the manufacture of amedicament for use in reducing ambulatory deterioration only in a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having a high baseline disability score accordingto the Kurtzke Expanded Disability Status Scale (EDSS). In anembodiment, the high baseline disability score is a baseline EDSS scoreof greater than 3.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for reducing ambulatorydeterioration only in a human patient diagnosed to be afflicted withrelapsing-remitting multiple sclerosis (RRMS) and having a high baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS). In an embodiment, the high baseline disability score is abaseline EDSS score of greater than 3.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to reduceambulatory deterioration only in a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS). In an embodiment, the high baselinedisability score is a baseline EDSS score of greater than 3.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havinga high baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS), which comprises: a) one or more unitdoses, each such unit dose comprising an amount of laquinimod thereof,wherein the amount of said laquinimod in said unit dose is effective,upon administration to said patient, to reduce ambulatory deteriorationin the patient, and b) a finished pharmaceutical container therefor,said container containing said unit dose or unit doses, said containerfurther containing or comprising labeling directing the use of saidpackage in the treatment of said patient. In an embodiment, the highbaseline disability score is a baseline EDSS score of greater than 3.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with RRMS and having impaired mobility,comprising periodically administering to only the patient diagnosed withRRMS and having impaired mobility an amount of laquinimod effective totreat the patient. In an embodiment, mobility is assessed by thepatient's Timed-25 foot walk test score.

In an embodiment, the mobility impairment is an ambulatory impairment.In another embodiment, the patient is not ambulatory.

In another embodiment, mobility is assessed by the MSWS-12 self-reportquestionnaire. In another embodiment, mobility is assessed by theAmbulation Index. In another embodiment, mobility is assessed by theSix-Minute Walk (6MW) Test. In yet another embodiment, mobility isassessed by the LEMMT Test.

The subject invention also provides a method of treating a human patientafflicted with RRMS, comprising a) diagnosing the patient as having amobility impairment as assessed by the patient's Timed-25 foot walk testscore, and b) administering to the patient an amount of laquinimodeffective to treat the patient only if the patient has been diagnosed ashaving a mobility impairment.

In an embodiment, the mobility impairment is an ambulatory impairment.In another embodiment, the patient is not ambulatory.

In one embodiment, the amount of laquinimod is effective to reduce thepatient's relapse rate. In another embodiment, the amount of laquinimodis effective to reduce the patient's accumulation of physicaldisability.

In one embodiment, the accumulation of physical disability is assessedby the patient's MSFC score. In another embodiment, the amount oflaquinimod is effective to reduce deterioration of the patient'sambulation. In another embodiment, after 24 months of periodicadministration of laquinimod, the patient's accumulation of physicaldisability is reduced as compared to a patient not receiving periodicadministration of laquinimod. In another embodiment, the accumulation ofphysical disability is assessed by the time to CDP as measured by EDSSscore. In another embodiment, the patient has a baseline EDSS score of3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score. Inanother embodiment, the patient has a baseline EDSS score of greaterthan 3.5, greater than 4.0, greater than 4.5, greater than 5.0, orgreater than 5.5, and CDP is a 1 point increase of the baseline EDSSscore. In another embodiment, the patient has a baseline EDSS score of5.5 or greater and CDP is a 0.5 point increase of the baseline EDSSscore.

In one embodiment, CDP is sustained for at least 3 months. In anotherembodiment, CDP is sustained for at least 6 months.

The subject invention also provides a method of reducing mobilitydeterioration in a human patient diagnosed to be afflicted with RRMS andhaving impaired mobility, comprising periodically administering to onlythe patient diagnosed with RRMS and having impaired mobility an amountof laquinimod effective to reduce mobility deterioration.

In an embodiment, the mobility impairment is an ambulatory impairment.In another embodiment, the patient is not ambulatory.

In an embodiment, mobility is assessed by the patient's Timed-25 footwalk test score.

In one embodiment, after 24 months of periodic administration oflaquinimod, deterioration of the patient's mobility is reduced ascompared to a patient not receiving periodic administration oflaquinimod. In another embodiment, the patient has been diagnosed with abaseline EDSS score of greater than 3.5, greater than 4.0, greater than4.5, greater than 5.0, or greater than 5.5. In another embodiment, thepatient has been diagnosed with a baseline EDSS score of 3.5-5.5.

In one embodiment, the patient is naïve to an RRMS treatment. In anotherembodiment, the patient is naïve to laquinimod treatment. In anotherembodiment, the patient is naïve to 0.3 mg/day laquinimod treatment. Inanother embodiment, the patient is naïve to 0.6 mg/day laquinimodtreatment. In another embodiment, the patient is naïve to 1.2 mg/daylaquinimod treatment.

In an embodiment, laquinimod is laquinimod sodium. In anotherembodiment, laquinimod is administered orally. In another embodiment,laquinimod is administered daily. In another embodiment, laquinimod isadministered at a daily dose of 0.1-2.5 mg laquinimod. In anotherembodiment, laquinimod is administered at a daily dose of 0.6 mglaquinimod. In another embodiment, the periodic administration is for aperiod of greater than 24 weeks.

In one embodiment, laquinimod is administered as monotherapy for RRMS.In another embodiment, laquinimod is administered as adjunct therapywith an other RRMS treatment. In another embodiment, the other RRMStreatment is administration of interferon beta 1-a, interferon beta 1-b,glatiramer acetate, mitoxantrone or natalizumab.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with RRMS and having impaired mobility.

In an embodiment, the mobility impairment is an ambulatory impairment.In another embodiment, the patient is not ambulatory.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for use in treating only ahuman patient diagnosed to be afflicted with RRMS and having impairedmobility.

In an embodiment, the mobility impairment is an ambulatory impairment.In another embodiment, the patient is not ambulatory.

In one embodiment, mobility is assessed by the patient's Timed-25 footwalk test score.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with RRMS and having impairedmobility.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with RRMS and having impaired mobility, which comprises: a)one or more unit doses, each such unit dose comprising an amount oflaquinimod thereof, wherein the amount of said laquinimod in said unitdose is effective, upon administration to said patient, to treat thepatient, and b) a finished pharmaceutical container therefor, saidcontainer containing said unit dose or unit doses, said containerfurther containing or comprising labeling directing the use of saidpackage in the treatment of said patient.

In one embodiment of the package or the therapeutic package as describedherein, the mobility impairment is an ambulatory impairment. In anotherembodiment, the patient is not ambulatory. In another embodiment, thepatient's mobility is assessed by the patient's Timed-25 foot walk testscore.

The subject invention also provides a method of treating a human patientdiagnosed to be afflicted with RRMS and having worsening MS, comprisingperiodically administering to only the patient diagnosed with RRMS andhaving worsening MS an amount of laquinimod effective to treat thepatient. In an embodiment, the patient has a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3.0. In one embodiment, laquinimod is laquinimod sodium. Inanother embodiment, laquinimod is administered orally. In anotherembodiment, laquinimod is administered daily. In another embodiment,laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. Inanother embodiment, laquinimod is administered at a daily dose of 0.6 mglaquinimod. In another embodiment, laquinimod is administered at a dailydose of 1.2 mg laquinimod.

In one embodiment, laquinimod is administered as monotherapy for RRMS.In another embodiment, laquinimod is administered as adjunct therapywith another RRMS treatment. In another embodiment, the other RRMStreatment is administration of interferon beta 1-a, interferon beta 1-b,glatiramer acetate, mitoxantrone or natalizumab.

The subject invention also provides laquinimod for the manufacture of amedicament for use in treating only a human patient diagnosed to beafflicted with relapsing-remitting multiple sclerosis (RRMS) and havingworsening MS.

The subject invention also provides a pharmaceutical compositioncomprising an effective amount of laquinimod for treating only a humanpatient diagnosed to be afflicted with relapsing-remitting multiplesclerosis (RRMS) and having worsening MS. In an embodiment of the use oflaquinimod or pharmaceutical composition, the patient has a baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS) of greater than 3.0.

The subject invention also provides a package comprising: a) apharmaceutical composition comprising an amount of laquinimod; and b)instruction for use of the pharmaceutical composition to treat only ahuman patient diagnosed to be afflicted with RRMS and having worseningMS.

The subject invention also provides a therapeutic package for dispensingto, or for use in dispensing to, only a human patient diagnosed to beafflicted with RRMS and having worsening MS, which comprises: a) one ormore unit doses, each such unit dose comprising an amount of laquinimodthereof, wherein the amount of said laquinimod in said unit dose iseffective, upon administration to said patient, to treat the patient,and b) a finished pharmaceutical container therefor, said containercontaining said unit dose or unit doses, said container furthercontaining or comprising labeling directing the use of said package inthe treatment of said patient.

For the foregoing embodiments, each embodiment disclosed herein iscontemplated as being applicable to each of the other disclosedembodiment.

A dosage unit may comprise a single compound or mixtures of compoundsthereof. A dosage unit can be prepared for oral dosage forms, such astablets, capsules, pills, powders, and granules.

Laquinimod can be administered in admixture with suitable pharmaceuticaldiluents, extenders, excipients, or carriers (collectively referred toherein as a pharmaceutically acceptable carrier) suitably selected withrespect to the intended form of administration and as consistent withconventional pharmaceutical practices. The unit may in a form suitablefor oral administration. Laquinimod can be administered alone but isgenerally mixed with a pharmaceutically acceptable carrier, andco-administered in the form of a tablet or capsule, liposome, or as anagglomerated powder. Examples of suitable solid carriers includelactose, sucrose, gelatin and agar. Capsule or tablets can be easilyformulated and can be made easy to swallow or chew; other solid formsinclude granules, and bulk powders. Tablets may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents flow-inducing agents, and melting agents.

Specific examples of the techniques, pharmaceutically acceptablecarriers and excipients that may be used to formulate oral dosage formsof the present invention are described, e.g., in U.S. Patent ApplicationPublication No. 2005/0192315, PCT International Application PublicationNos. WO 2005/074899, WO 2007/047863, and 2007/146248.

General techniques and compositions for making dosage forms useful inthe present invention are described in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). These references in their entireties are herebyincorporated by reference into this application.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,dicalcium phosphate, calcium sulfate, mannitol, sorbitol,microcrystalline cellulose and the like. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornstarch, natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Lubricants used in these dosage forms include sodiumoleate, sodium stearate, sodium benzoate, sodium acetate, sodiumchloride, stearic acid, sodium stearyl fumarate, talc and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, croscarmellose sodium, sodium starchglycolate and the like.

TERMS

As used herein, and unless stated otherwise, each of the following termsshall have the definition set forth below.

As used herein, “laquinimod” means laquinimod acid or a pharmaceuticallyacceptable salt thereof. A “pharmaceutically acceptable salt” oflaquinimod as used in this application includes lithium, sodium,potassium, magnesium, calcium, manganese, copper, zinc, aluminum andiron. Salt formulations of laquinimod and the process for preparing thesame are described, e.g., in U.S. Patent Application Publication No.2005/0192315 and PCT International Application Publication No. WO2005/074899, which are hereby incorporated by reference into thisapplication.

As used herein, an “amount” or “dose” of laquinimod as measured inmilligrams refers to the milligrams of laquinimod acid present in apreparation, regardless of the form of the preparation. A “dose of 0.6mg laquinimod” means the amount of laquinimod acid in a preparation is0.6 mg, regardless of the form of the preparation. Thus, when in theform of a salt, e.g. a laquinimod sodium salt, the weight of the saltform necessary to provide a dose of 0.6 mg laquinimod would be greaterthan 0.6 mg (e.g., 0.64 mg) due to the presence of the additional saltion.

As used herein, “about” in the context of a numerical value or rangemeans±10% of the numerical value or range recited or claimed.

As used herein, a “unit dose”, “unit doses” and “unit dosage form(s)”mean a single drug administration entity/entities.

As used herein, a subject at “baseline” is as subject prior toadministration of laquinimod in a therapy as described herein.

As used herein, a subject who is “naïve” to a particular therapy is asubject who has not previously received said therapy.

As used herein, a human patient “diagnosed to be afflicted withrelapsing-remitting multiple sclerosis” means a human patient who hasbeen clinically diagnosed to have relapsing-remitting multiplesclerosis. As used herein, “Relapsing-Remitting Multiple Sclerosis” or“RRMS” is characterized by clearly defined acute attacks with fullrecovery or with sequelae and residual deficit upon recovery (Lublin,1996) Relapsing-remitting multiple sclerosis can be diagnosed, e.g., asdefined by the Revised McDonald Criteria (Polman 2011).

As used herein, a human patient “diagnosed to have” a high baselinedisability score according to the Kurtzke Expanded Disability StatusScale (EDSS), means a human patient who has been clinically diagnosed tohave “a high baseline disability score”, which, as used herein, means abaseline EDSS score of ≧3, >3, ≧3.5, >3.5, ≧4, >4, ≧4.5, >4.5, ≧5, >5,≧5.5, or >5.5. Similarly, as used herein, a human patient “diagnosed tohave” a baseline disability score according to the Kurtzke ExpandedDisability Status Scale (EDSS) of greater than 3.0 means a human patientwho has been clinically diagnosed to have a baseline EDSS score of >3.

As used herein, “administering to a/the human patient” means the givingof, dispensing of, or application of medicines, drugs, or remedies tothe human patient to relieve, cure, or reduce the symptoms associatedwith a disease, disorder or condition, e.g., a pathological condition.As used herein, “administering only to a/the human patient . . . ” meansthe giving of, dispensing of, or application of medicines, drugs, orremedies to only the human patient population identified to theexclusion of all other potential patient populations. The administrationcan be periodic administration. As used herein, “periodicadministration” means repeated/recurrent administration separated by aperiod of time. The period of time between administrations is preferablyconsistent from time to time. Periodic administration can includeadministration, e.g., once daily, twice daily, three times daily, fourtimes daily, weekly, twice weekly, three times weekly, four times weeklyand so on, etc.

As used herein, “treating” (or treat) encompasses, e.g., inducinginhibition, regression, or stasis of a disease or disorder, orlessening, suppressing, inhibiting, reducing the severity of,eliminating or substantially eliminating, or ameliorating a symptom ofthe disease or disorder. As used herein, “inhibition” of diseaseprogression or disease complication in a subject means preventing orreducing the disease progression and/or disease complication in thesubject.

A “symptom” associated with a disease or disorder includes any clinicalor laboratory manifestation associated with the disease or disorder andis not limited to what the subject can feel or observe.

As used herein, “effective” when referring to an amount of laquinimodrefers to the quantity of laquinimod that is sufficient to yield adesired therapeutic response without undue adverse side effects (such astoxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of this invention.

As used herein, “Confirmed Relapse” is defined as the appearance of oneor more new neurological abnormalities or the reappearance of one ormore previously observed neurological abnormalities wherein the changein clinical state lasts at least 48 hours and is immediately preceded byan improving neurological state of at least thirty (30) days from onsetof previous relapse. This criterion is different from the clinicaldefinition of relapse which requires only 24 hours duration of symptoms.(EMEA Guideline, 2006) Since “in study” relapse definition must besupported by an objective neurological evaluation as discussed below, aneurological deficit must sustain long enough to eliminatepseudo-relapses.

An event is a relapse only when the subject's symptoms are accompaniedby observed objective neurological changes, consistent with at least oneof the following: an increase of at least 0.5 in the EDSS score ascompared to the previous evaluation, an increase of one grade in thescore of 2 or more of the 7 FS functions as compared to the previousevaluation, or an increase of 2 grades in the score of one FS ascompared to the previous evaluation.

In addition, the subject must not be undergoing any acute metabolicchanges such as fever or other medical abnormality. A change inbowel/bladder function or in cognitive function must not be entirelyresponsible for the changes in EDSS or FS scores.

As used herein, “Relapse Rate” is the number of confirmed relapses perunit time. “Annualized relapse rate” or “ARR” is the mean value of thenumber of confirmed relapses of each patient multiplied by 365 anddivided by the number of days that patient is on the study drug.

As used herein, “Expanded Disability Status Scale” or “EDSS” is a ratingsystem that is frequently used for classifying and standardizing thecondition of people with multiple sclerosis. The score ranges from 0.0representing a normal neurological exam to 10.0 representing death dueto MS. The score is based upon neurological testing and examination offunctional systems (FS), which are areas of the central nervous systemwhich control bodily functions. The functional systems are: Pyramidal(ability to walk), Cerebellar (coordination), Brain stem (speech andswallowing), Sensory (touch and pain), Bowel and bladder functions,Visual, Mental, and Other (includes any other neurological findings dueto MS). (Kurtzke J F, 1983)

As used herein, a “confirmed progression” of EDSS, or “confirmed diseaseprogression” as measured by EDSS score is defined as a 1 point increasefrom baseline EDSS if baseline EDSS was between 0 and 5.0, or a 0.5point increase if baseline EDSS was 5.5. In order to be considered aconfirmed progression, the change (either 1 point or 0.5 points) must besustained for at least 3 months. In addition, confirmation ofprogression cannot be made during a relapse.

As used herein, an “adverse event” or “AE” means any untoward medicaloccurrence in a clinical trial subject administered a medicinal productand which does not have a causal relationship with the treatment. Anadverse event can therefore be any unfavorable and unintended signincluding an abnormal laboratory finding, symptom, or diseasestemporally associated with the use of an investigational medicinalproduct, whether or not considered related to the investigationalmedicinal product.

As used herein, “Ambulation Index” or “AI” is a rating scale developedby Hauser et al. to assess mobility by evaluating the time and degree ofassistance required to walk 25 feet. Scores range from 0 (asymptomaticand fully active) to 10 (bedridden). The patient is asked to walk amarked 25-foot course as quickly and safely as possible. The examinerrecords the time and type of assistance (e.g., cane, walker, crutches)needed. (Hauser, 1983)

As used herein “mobility” refers to any ability relating towalking/ambulation, walking speed, gait, strength of leg muscles, legfunction and the ability to move with or without assistance. Mobilitycan be evaluated by one or more of several tests including but notlimited to Ambulation Index, Timed 25 foot walk, Six-Minute Walk (6MW),Lower Extremity Manual Muscle Test (LEMMT), and EDSS. Mobility can alsobe reported by the subject, for example by questionnaires, including butnot limited to 12-Item Multiple Sclerosis Walking Scale (MSWS-12).“Impaired Mobility” as used herein refers to any impairment, difficultyor disability relating to mobility.

The “Six-Minute Walk (6MW) Test” is a commonly used test developed toassess exercise capacity in patients with COPD (Guyatt, 1985). It hasbeen used also to measure mobility in multiple sclerosis patients(Clinical Trials Website).

The “Timed-25 Foot Walk” or “T25-FW” is a quantitative mobility and legfunction performance test based on a timed 25-walk. The patient isdirected to one end of a clearly marked 25-foot course and is instructedto walk 25 feet as quickly as possible, but safely. The time iscalculated from the initiation of the instruction to start and ends whenthe patient has reached the 25-foot mark. The task is immediatelyadministered again by having the patient walk back the same distance.Patients may use assistive devices when doing this task. The score forthe T25-FW is the average of the two completed trials. This score can beused individually or used as part of the MSFC composite score (NationalMS Society Website).

As used herein, “EQ-5D” is a standardized questionnaire instrument foruse as a measure of health outcome applicable to a range of healthconditions and treatments. It provides a simple descriptive profile anda single index value for health status that can be used in the clinicaland economic evaluation of health care as well as population healthsurveys. EQ-5D was developed by the “EuroQoL” Group which comprises anetwork of international, multilingual, multidisciplinary researchers,originally from seven centers in England, Finland, the Netherlands,Norway and Sweden. The EQ-5D questionnaire is in the public domain andcan be obtained from EuroQoL.

As used herein, “Gd-enhancing lesion” refers to lesions that result froma breakdown of the blood-brain barrier, which appear in contrast studiesusing gadolinium contrast agents. Gadolinium enhancement providesinformation as to the age of a lesion, as Gd-enhancing lesions typicallyoccur within a six week period of lesion formation.

As used herein, “Magnetization Transfer Imaging” or “MTI” is based onthe magnetization interaction (through dipolar and/or chemical exchange)between bulk water protons and macromolecular protons. By applying anoff resonance radio frequency pulse to the macromolecular protons, thesaturation of these protons is then transferred to the bulk waterprotons. The result is a decrease in signal (the net magnetization ofvisible protons is reduced), depending on the magnitude of MT betweentissue macromolecules and bulk water. “MT” or “Magnetization Transfer”refers to the transfer of longitudinal magnetization from the hydrogennuclei of water that have restricted motion to the hydrogen nuclei ofwater that moves with many degrees of freedom. With MTI, the presence orabsence of macromolecules (e.g. in membranes or brain tissue) can beseen. (Mehta, 1996; Grossman, 1994)

As used herein, “Magnetization Resonance Spectroscopy” or “MRS” is aspecialized technique associated with magnetic resonance imaging (MRI).MRS is used to measure the levels of different metabolites in bodytissues. The MR signal produces a spectrum of resonances that correspondto different molecular arrangements of the isotope being “excited”. Thissignature is used to diagnose certain metabolic disorders, especiallythose affecting the brain, (Rosen, 2007) as well as to provideinformation on tumor metabolism. (Golder, 2007)

As used herein, “Modified Fatigue Impact Scale” or “MFIS” is a validatedspecific subject-reported outcome measure developed to evaluate theimpact of fatigue on the lives of people with MS. This instrumentprovides an assessment of the effects of fatigue in terms of physical,cognitive, and psychosocial functioning. The full-length MFIS consistsof 21 items while the abbreviated version has 5 items. (Fisk et al,1994)

As used herein, “MS Functional Composite” or “MSFC” is a clinicaloutcome measure for MS. The MSFC comprises quantitative functionalmeasures of three key clinical dimensions of MS: legfunction/ambulation, arm/hand function, and cognitive function. Scoreson component measures are converted to standard scores (z-scores), whichare averaged to form a single MSFC score. (Fischer, 1999)

As used herein, “SF-36” is a multi-purpose, short-form health surveywith 36 questions which yields an 8-scale profile of functional healthand well-being scores as well as psychometrically-based physical andmental health summary measures and a preference-based health utilityindex. It is a generic measure, as opposed to one that targets aspecific age, disease, or treatment group. The survey is developed byand can be obtained from QualityMetric, Inc. of Providence, R.I.

As used herein, “T1-weighted MRI image” refers to an MR-image thatemphasizes T1 contrast by which lesions may be visualized. Abnormalareas in a T1-weighted MRI image are “hypointense” and appear as darkspots. These spots are generally older lesions.

“T2-weighted MRI image” refers to an MR-image that emphasizes T2contrast by which lesions may be visualized. T2 lesions represent newinflammatory activity.

As used herein, a “pharmaceutically acceptable carrier” refers to acarrier or excipient that is suitable for use with humans and/or animalswithout undue adverse side effects (such as toxicity, irritation, andallergic response) commensurate with a reasonable benefit/risk ratio. Itcan be a pharmaceutically acceptable solvent, suspending agent orvehicle, for delivering the instant compounds to the subject.

It is understood that where a parameter range is provided, all integerswithin that range, and tenths thereof, are also provided by theinvention. For example, “0.1-2.5 mg” includes 0.1 mg, 0.2 mg, 0.3 mg,0.4 mg, 0.5 mg etc. up to 2.5 mg.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS Example 1 Clinical Trial (Phase III)—Assessment ofOral Laquinimod in Preventing Progression of MS

A multinational (24 countries), multicenter (approximately 139 sites),randomized, double-blinded, parallel-group, placebo-controlled clinicaltrial (“ALLEGRO” or MS-LAQ-301) was conducted to evaluate the efficacy,safety and tolerability of daily oral administration of laquinimod 0.6mg in subjects with relapsing remitting multiple sclerosis (RRMS) for a24 months duration.

One thousand one hundred and six (1106) patients were equally randomizedto either laquinimod 0.6 mg or placebo and treated in a double-blindmanner and baseline characteristics were balanced between groups. Theprimary endpoint of the study was the number of confirmed relapsesduring the double-blind treatment period, which corresponds to theannualized relapse rate (ARR—number of relapses divided by totalexposure of all patients). Secondary endpoints included disability asmeasured by Expanded Disability Status Scale (EDSS) changes confirmed at3 months, and cumulative number of gadolinium enhancing (GdE) andnew/enlarging T2 MRI lesions.

Study Duration

Screening Phase: 1 Month.

Double blind treatment phase: 24 months of once-daily oraladministration of daily dose of 0.6 mg laquinimod or matching placebo.

Upon blinded variance and power reassessment of the populationprogression (planned prior to first subject completes the 20 months oftreatment), the double blind study duration may be extended to 30months. This is planned in order to enhance the statistical power todetect the effect of laquinimod on disability accumulation. Therecommendation to extend the study duration is based on a pre-definedrule.

Study Design

Eligible subjects were equally randomized 1:1 into one of the followingtreatment arms:

-   -   1. Laquinimod capsules 0.6 mg: One 0.6 mg laquinimod capsule was        administered orally once daily. The 0.6 mg laquinimod capsules        contain 0.6 mg of Laquinimod Acid per capsule with meglumine,        and were manufactured according to the method disclosed in PCT        International Application Publication No. WO/2007/146248,        published Dec. 21, 2007 (see, page 10, line 5 to page 11, line        3).    -   2. Matching placebo for laquinimod arm: one capsule is        administered once daily.

Subjects were evaluated at study sites for 12 scheduled visits of thedouble blind phase at months: −1 (screening), 0 (baseline), 1, 2, 3, 6,9, 12, 15, 18, 21 and 24 (termination/early discontinuation). In case ofthe 6 months extended study, subjects were evaluated at study sites atmonths 27 and 30 (termination/early discontinuation of extended study),in this case month 24 was a regular scheduled visit.

EDSS was assessed every 3 months, MSFC every 6 months, and MRI wasperformed annually in all patients. A subgroup of patients (n=189)underwent additional MRI scans at months 3 and 6. Subjects successfullycompleting the study were offered the opportunity to enter into a 1-yearopen label extension. Patients who discontinued the study underwent afinal termination visit and were not further evaluated, except for thosewho discontinued due to adverse events.

The following assessments were performed at specified time points:

-   1. Vital signs were measured at each study visit.-   2. A physical examination is performed at months −1 (screening), 0    (baseline) 1, 3, 6, 12, 18 and 24 (termination/early discontinuation    core study). In case of the 6 months extended study, additional    examination was performed at month 30 (termination/early    discontinuation of extended study).-   3. The following safety clinical laboratory tests were performed:    -   a. Complete blood count (CBC) with differential—at all scheduled        visits. A reticulocyte count was added to the CBC at months 0        (baseline) and 24/30 (termination/early discontinuation).    -   b. Serum chemistry (including electrolytes, liver enzymes,        direct and total bilirubin and pancreatic amylase and CPK), and        urinalysis—at all scheduled visits.    -   c. A rapid urine β-hCG test was performed in women of        child-bearing potential at baseline (month 0) and at each        scheduled study visit thereafter (at site).    -   d. β-hCG in women of child-bearing potential was performed at        all scheduled visits.    -   e. Starting after visit Month 3 a rapid urine β-hCG test was        performed in women of child-bearing potential every 28 (±2)        days. The subject was contacted by telephone within 72 hours        after the test was scheduled to be performed and asked specific        questions regarding the test. In case of suspected pregnancy        (positive urine β-hCG test result), the caller made sure that        the study drug has been discontinued and the subject was        instructed to arrive at the site as soon as possible with all        study drugs.-   4. Markers of inflammation (serum conventional C-reactive protein    and fibrinogen)—at screening, baseline and all scheduled visits    thereafter.-   5. During the first 3 months periodical phone calls were placed by    the site personnel every two weeks. A list of predefined questions    relating to signs/symptoms suggestive of vascular thrombosis was    presented to the subjects.-   6. ECG was performed at months −1 (screening; additional recording,    up to 30 minutes apart is performed if QT_(c) is less than 450    msec), (baseline; three recordings, 15 minutes apart), 1, 2, 3, 6,    12, 18 and 24 (termination/early discontinuation). In case of the 6    months extended study, ECG is performed at month 30    (termination/early discontinuation of the extended study).-   7. Chest X-ray is performed at months −1 (screening), (if not    performed within 7 months prior to the screening visit).-   8. Adverse Events (AEs) are monitored throughout the study.-   9. Concomitant medications are monitored throughout the study.-   10. Neurological evaluations, including Expanded Disability Status    Scale (EDSS), 25 foot walk test/Ambulation Index (AI), Functional    systems (FS) are performed at months −1 (screening), 0 (baseline)    and every 3 months during the study and the extended study period.-   11. MS functional Composite (MSFC) was assessed at months −1    (screening) (three practices for training purposes only), at month 0    (baseline), 6, 12, 18 and 24 (termination/early discontinuation). In    case of the 6 months extended study, the last MSFC was performed at    months 30 (termination/early discontinuation of the extended study).-   12. Subject-reported fatigue was assessed by the Modified Fatigue    Impact Scale (MFIS) at months 0, 6, 12, 18, and 24    (termination/early discontinuation). In case of the 6 months    extended study, additional MFIS was performed at month 30    (termination/early discontinuation of the extended study).-   13. The general health status was assessed by the EuroQoL (EQ5D)    questionnaire at month 0 (baseline) and month 24 (termination/early    discontinuation of the study). In case of the 6 months extended    study, the last EuroQoL (EQ5D) was performed at month 30    (termination/early discontinuation of the extended study) instead of    month 24.-   14. The general health status was assessed by the Short-Form general    health survey (SF-36) subject-reported questionnaire at month 0    (baseline) and every 6 months thereafter, until termination/early    discontinuation.-   15. The subject underwent 5 assessments of binocular low-contrast    visual acuity using the 100%, 2.5% and 1.25% contrast level charts    [Sloan letter or Tumbling-E] in each assessment, at months 0    (baseline), 6, 12, 18 and 24 (termination/early discontinuation). In    case of extending the study for 6 months, additional binocular    low-contrast visual acuity assessment is performed at month 30    (termination/early discontinuation of the extended study).-   16. Serum samples were collected from all subjects in order to    investigate the potential mechanism of action of laquinimod and    additional biomarkers of inflammation and potential biomarkers of MS    disease at months: 0, 1, 12 and 24. In case of extending the study    for 6 months the last serum sample is performed at month 30    (termination/early discontinuation of the extended study) instead of    month 24.-   17. The subjects underwent 3 MRI scans at months 0 (baseline), 12    and 24 (termination/early discontinuation). In case of the 6 months    extended study, an additional MRI was performed at month 30    (termination/early discontinuation of the extended study).-   18. Population PK study (PPK): Blood samples for PPK evaluation were    collected from all subjects at months 1, 12 and 24. In case of    extending the study for 6 months the last PPK evaluation was    performed at month 30 (termination/early discontinuation of the    extended study) instead of month 24.-   19. Relapses were confirmed/monitored through the study. Since the    “in study” relapse definition must be supported by an objective    neurological evaluation, a neurological deficit must sustain long    enough to eliminate pseudo-relapses. Therefore, in this clinical    trial, a relapse was the appearance of one or more new neurological    abnormalities or the reappearance of one or more previously observed    neurological abnormalities wherein the change in clinical state    lasts at least 48 hours and is immediately preceded by an improving    neurological state of at least thirty (30) days from onset of    previous relapse.-   20. The allowed treatment for a relapse was intravenous    Methylprednisolone 1 gr/day for up to 5 consecutive days.

Baseline Disease Characteristics of Patients is shown in Table 1 below:

TABLE 1 Laquinimod 0.6 mg Placebo All Characteristic daily (n = 550) (n= 556) (N = 1106) Relapses in last year prior to screening Mean (SD) 1.2(0.7) 1.3 (0.7) 1.2 (0.7) Median 1.0 1.0 1.0 Range 0.0 to 4.0 0.0 to 5.00.0 to 5.0 Relapses in last 2 years prior to screening Mean (SD) 1.9(1.0) 1.9 (1.0) 1.9 (1.0) Median 2.0 2.0 2.0 Range 0.0 to 7.0 0.0 to 7.00.0 to 7.0 EDSS Mean (SD) 2.6 (1.3) 2.6 (1.3) 2.6 (1.3) Median 2.5 2.52.5 Range 0.0-5.5  0.0-6.0  0.0 to 6.0 Time from first symptom (years)Mean (SD) 8.7 (6.9) 8.7 (6.7) 8.6 (6.8) Median 7.0 7.0 7.0 Range  0.5 to34.5  0.4 to 32.8  0.4 to 34.5 History of disease- 206 212 418 modifyingtreatment Number (%) 210 (38.2%) 221 (39.7%) 431 (38.9%) Interferonbeta-1a 132 123 Interferon beta-1b 76 82 Interferon 4 3 Glatirameracetate 84 89 Number of T1 GdE lesions Mean (SD) 1.7 (3.9) 2.0 (5.7) 1.9(4.9) Median 0.0 0.0 0.0 Range 0.0-30.0 0.0-84.0 0.0-84.0 T2 lesionvolume, mm³ Geometric mean (CV %) 7.27 (46.1) 7.31 (44.8) 7.29 (45.5)Median 6.3 6.8 Range  0.0 to 82.1  0.0 to 77.5 Normalized brain volume,cm³ Mean (SD) 1578.9 (94.3) 1584.7 (92.1) 1581.3 (93.2) Median 1578.01590 1583.0 Range 1312.0 to 1823.0 1299.0 to 1824.0 1299.0 to 1824.0Re-Consent Criteria

Upon a confirmed diagnosis of MS relapse, (as defined in the protocol)or an increase in EDSS in ≦2.0 points, sustained for ≧3 months, thefollowing actions were taken:

-   1. The subject was reminded of the current available MS medications    and the opportunity to terminate the study as written in the    informed consent form.-   2. The subject was requested to re-sign an informed consent form if    he/she chooses to continue to participate in the study, in the same    treatment assignment.

Safety stopping rules were set in place for the management of: 1)elevated liver enzymes, 2) inflammatory events, 3) thrombotic events and4) pancreatitis.

Ancillary Studies:

-   1. Frequent MRI (selected countries and sites only): The cumulative    number of T₁-Gd enhancing lesions taken from scans obtained at    months 0, 3, 6, 12, and 24, and in case the study is be    extended, 30. Additional MRIs for the ancillary study are performed    at months 3 and 6.-   2. Magnetization Transfer (MT) (selected countries and sites only):    the change from baseline to month 12 and 24/30 months in    magnetization transfer MRI. MT was assessed at months 0 (baseline),    12 and 24 (termination/early discontinuation). In case of the 6    months extended study, the last MT was performed at month 30    (termination/early discontinuation of the extended study) instead of    month 24.-   3. Magnetization Resonance Spectroscopy (MRS) (selected countries    and sites only): Change from baseline to 24/30 in Magnetic Resonance    Spectroscopy (NAAS: Cr ratio in lesions, normally-appearing white    matter). MRS was assessed at months 0 (baseline), and 24    (termination/early discontinuation). In case of the 6 months    extended study, the last MRS was performed at month 30    (termination/early discontinuation of the extended study) instead of    month 24.-   4. Pharmacogenetic (PGx) assessment: Blood samples for PGx    parameters were collected from all subjects at screening.-   5. Brain atrophy, as defined by the percentage of change from one    scan to the subsequent scan in brain volume, in addition to the    measurements done in the main study (Frequent MRI Cohort).-   6. Whole blood and serum samples (selected countries and sites only)    were collected for evaluation of the immunological response to    treatment with laquinimod and further investigation of the potential    mechanism of action. Whole blood samples were collected at months:    0, 1, 3, 6, 12 and 24. Serum samples were collected at month: 0, 1,    6, 12 and 24 (even if the study is extended to month 30).-   7. Relationship between PGx and response to laquinimod in terms of    clinical, MRI and safety parameters.    Inclusion/Exclusion Criteria    Inclusion Criteria-   1. Subjects must have a confirmed and documented diagnosis as    defined by the Revised McDonald Criteria (Polman, 2005), with    relapsing-remitting disease course.-   2. Subjects must be ambulatory with converted Kurtzke EDSS score of    0-5.5.-   3. Subjects must be in a stable neurological condition and free of    corticosteroid treatment [intravenous (iv), intramuscular (im)    and/or per os (po)] 30 days prior to screening (month −1).-   4. Subjects must have experienced one of the following:    -   a. At least one documented relapse in the 12 months prior to        screening.    -   b. At least two documented relapses in the 24 months prior to        screening.    -   c. One documented relapse between 12 and 24 months prior to        screening with at least one documented T1-Gd enhancing lesion in        an MRI performed within 12 months prior to screening.-   5. Subjects must be between 18 and 55 years of age, inclusive.-   6. Subjects must have disease duration of at least 6 months (from    the first symptom) prior to screening.-   7. Women of child-bearing potential must practice an acceptable    method of birth control. Acceptable method of birth control in this    study include: surgical sterilization, intrauterine devices, oral    contraceptive, contraceptive patch, long-acting injectable    contraceptive, partner's vasectomy or double barrier method (condom    or diaphragm with spermicide).-   8. Subjects must be able to sign and date a written informed consent    prior to entering the study.-   9. Subjects must be willing and able to comply with the protocol    requirements for the duration of the study.    Exclusion Criteria-   1. Subjects with progressive forms of MS.-   2 An onset of relapse, unstable neurological condition or any    treatment with corticosteroids [(iv), intramuscular (im) and/or per    os (po)] or ACTH between months −1 (screening) and 0 (baseline).-   3. Use of experimental or investigational drugs, and/or    participation in drug clinical studies within the 6 months prior to    screening.-   4. Use of immunosuppressive including mitoxantrone (Novantrone®) or    cytotoxic agents within 6 months prior to screening visit.-   5. Previous use of any one of the following: natalizumab (Tysabri®),    caldribine, laquinimod.-   6. Previous treatment with glatiramer acetate (Copaxone®)    Interferon-β (either 1a or 1b) or intravenous immunoglobulin (IVIG)    within 2 months prior to screening visit.-   7. Systemic corticosteroid treatment of ≧30 consecutive days    duration within 2 months prior to screening visit.-   8. Previous total body irradiation or total lymphoid irradiation.-   9. Previous stem cell treatment, autologous bone marrow    transplantation or allogenic bone marrow transplantation.-   10. A known history of tuberculosis.-   11. Acute infection two weeks prior to baseline visit.-   12. Major trauma or surgery two weeks prior to baseline.-   13. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline    visit (1 month for fluoxetine).-   14. Use of amiodarone within 2 years prior to screening visit.-   15. Pregnancy or breastfeeding.-   16. A ≧3×ULN serum elevation of either ALT or AST at screening.-   17. Serum direct bilirubin which is 2×ULN at screening.-   18. A QTc interval which is 450 msec (according to machine output)    obtained from:    -   a. Two ECG recordings at screening visit, or    -   b. The mean value calculated from 3 baseline ECG recordings.-   19. Subjects with clinically significant or unstable medical or    surgical condition that would preclude safe and complete study    participation, as determined by medical history, physical    examination, ECG, laboratory tests or chest X-ray. Such conditions    may include:    -   a. A cardiovascular or pulmonary disorder that cannot be        well-controlled by standard treatment permitted by the study        protocol.    -   b. A gastrointestinal disorder that may affect the absorption of        study medication.    -   c. Renal or metabolic diseases.    -   d. Any form of chronic liver disease.    -   e. Known human immunodeficiency virus (HIV positive status.    -   f. A family history of Long-QT syndrome.    -   g. A history of drug and/or alcohol abuse.    -   h. Major psychiatric disorder.-   20. A known history of sensitivity to Gd.-   21. Inability to successfully undergo MRI scanning.-   22. Known drug hypersensitivity that would preclude administration    of laquinimod, such as hypersensitivity to: mannitol, meglumine or    sodium stearyl fumarate.    Outcome Measures

Neurological evaluations, including safety assessments, were performedat screening, baseline and every three months up to month 24. Patientneurological assessments and general medical evaluations were conductedby two neurologists in order to minimize the possibility of unblinding;a specially trained and certified examining neurologist assessedneurological condition, and the treating neurologist determined whethera subject had experienced a relapse based on EDSS/Functional Systemsscores.

The primary endpoint was the number of confirmed relapses during thedouble-blind study period. A relapse was defined as the appearance ofone or more new neurological abnormalities or the reappearance of one ormore previously observed neurological abnormalities lasting for at least48 hours and after an improved neurological state for at least 30 days.An event was counted as a relapse if the subject's symptoms wereaccompanied by observed objective neurological changes consistent withat least one of the following: an increase of at least 0.5 in the EDSSscore; an increase of one grade in two or more of the seven functionalsystems; or an increase of two grades in one functional system.Standardized treatment of relapses was intravenous methylprednisolone 1g/day for up to five consecutive days based on the treatingneurologist's decision.

Secondary endpoints were disability progression as measured by the EDSSand the Multiple Sclerosis Functional Composite (MSFC). Confirmeddisability progression was defined as an increase of ≧1.0 EDSS pointfrom baseline if baseline EDSS was between 0 and 5.0, or an increase of≧0.5 point if baseline EDSS was ≧5.5. In order to confirm EDSSprogression, these increases had to be sustained for at least threemonths. Additional predefined disability endpoints include theproportion of patients without confirmed disability progression at 24months; confirmed disability progression (defined as change in EDSSscores ≧1.0 points for baseline EDSS 0 to 5.0 or ≧5.5) sustained for sixmonths; the accumulation of physical disability as measured by mean EDSSand the mean change in EDSS from baseline to last observed value (LOV).

For the MSFC, the measure was the total MSFC z score at 24 months(including patients who terminated after 12 months). The 9-hole peg test(9HPT) and the Paced Auditory Serial Addition Test (PASAT) wereperformed three times at screening to reduce confounding trainingeffects during the trial.

MRI related secondary endpoints were the cumulative number of GdElesions at months 12 and 24; and the cumulative number of new T2 lesions(relative to previous scan) at months 12 and 24; MRI exploratoryendpoints included percent change of brain volume using SIENA.

Additional MRI methodological details are as follows: In all patients,MRI scans were performed at 0, 12, and 24 months. Before a site couldenroll study participants they were required to image a volunteerpatient with definite MS twice with repositioning according to a strictstudy imaging protocol using scanners with a minimum field strength of1.5 T. Fast/turbo spin echo (repetition time [TR]=2200-3500 ms, echotime [TE]=14-50/90-120 ms, echo train length=2-7, slice thickness=3 mm,and contiguous axial slices=44) sequences were used to obtain protondensity and T2-weighted images. High resolution pre-contrast 3DT1-weighted sequences (TR=8-15 ms, TE=3-5 ms, inversion time=1.1 s,number of slices 160, slice thickness 1.2 mm, flip angle [FA]=10-15,orientation sagittal) were acquired for quantification of brain atrophy.Finally, T1-weighted images (1.5 T scanners: conventional spin echosequence; TR=600-650 ms, TE=10-20 ms, slice thickness=3 mm, andcontiguous axial slices=44; 3.0 T scanners: 3D sequence; TR=5-9 ms,TE=2-5 ms, FA=15, slice thickness=3 mm, and contiguous axial slices=44)were obtained 5 minutes after injection of 0.1 mmol/kg of gadolinium. Aseries of axial, coronal, and sagittal images was obtained to create anaxial reference scan for subsequent careful repositioning of eachpatient at the follow-up session. Axial slices were positioned to runparallel to a line joining the most inferioanterior and inferioposteriorparts of the corpus callosum.

Image quality was reviewed at the MRI-AC using predetermined criteria.The identification of GdE and T2-hyperintense lesions was done byconsensus of two experienced observers. The number of total and new GdElesions and new/enlarging T2-hyperintense lesions were counted. Theidentified lesions were then outlined by trained technicians using asemiautomated segmentation technique based on local thresholding (Jim4.0; Xinapse System, Leicester, UK) and lesion volumes were calculatedautomatically. Percentage brain volume changes and cross-sectionalnormalized brain volumes were measured on postcontrast T1-weightedimages, with Structural Image Evaluation of Normalized Atrophy (SIENA)software and a cross-sectional method (SIENAX) (available from the FMRIBSoftware Library, Oxford University, Oxford, UK;http://www.fmrib.ox.ac.uk/analysis/research/siena/siena).

Primary Outcome Measure

The number of confirmed relapses (and Annualized relapse rate) duringthe double blind study period.

Secondary Outcome Measures

-   1. Accumulation of physical disability measured by the time to    confirmed progression of EDSS during the study period (A confirmed    progression of EDSS is defined as a 1 point increase from baseline    on EDSS score if baseline EDSS was between 0 and 5.0, or a 0.5 point    increase if the baseline EDSS was 5.5, confirmed 3 months later.    Progression cannot be confirmed during a relapse).-   2. Disability, as assessed by the MSFC score at the end of the    treatment period (month 24/30).-   3. The cumulative number of new T2 lesions on scans taken on months    12 and 24 (and 30 in the case of the 6 months extended study).-   4. The cumulative number of enhancing lesions on T1-weighted images    taken on months 12 and 24 (and 30 in case of extending the study for    6 months.)    Safety and Tolerability Outcome Measures-   1. Adverse events.-   2. Vital signs.-   3. Weight.-   4. Physical examination.-   5. Electrocardiogram (ECG) findings.-   6. Clinical laboratory parameters.-   7. Proportion of subjects (%) who prematurely discontinued from the    study, reason of discontinuation and the time to withdrawal.-   8. Proportion of subjects (%) who prematurely discontinued form the    study due to AEs and the time to withdrawal.    Additional Exploratory Endpoints

The following assessments are performed in an exploratory manner:

-   1. To assess the cumulative number of new hypointense lesions on    enhanced T₁ scans at months 12 and 24 (and 30 in case of extending    the study for 6 months).-   2. Subject-reported fatigue as assessed by the Modified Fatigue    Impact Scale (MFIS).-   3. General health status by the EuroQoL (EQ5D) questionnaire.-   4. The general health status assessed by the Short-Form general    health survey (SF-36) subject-reported questionnaire.-   5. The time to the first confirmed relapse during the study period.-   6. The rate of confirmed relapses during the study period, requiring    hospitalization and/or IV steroids.-   7. The proportion of relapse free subjects.-   8. The change in T2-lesion volume as defined by the change from    baseline to month 12, from month 12 to month 24/30 and from baseline    to month 24/30.-   9. The change in T₁-hypointense lesion volume as defined by the    change from baseline to month 12, from month 12 to month 24/30 and    from baseline to month 24/30.-   10. Brain atrophy as defined by the percentage of change from    baseline to month 12, from month 12 to month 24/30 and from baseline    to month 24/30 in brain volume.-   11. Serum samples are collected from all subjects in order to    investigate the potential mechanism of action of laquinimod and    additional biomarkers of inflammation and potential biomarkers of MS    disease. These samples are collected at months: 0 (baseline), 1, 12    and 24 (even if the study is extended to month 30).-   12. Population PK—fitness of a population model to different    covariates is evaluated. (covariates such as: gender, age,    concomitant medications, weight, AE profile, habits).-   13. The change from baseline to month 24/30 (termination/early    discontinuation) in binocular visual acuity, as assessed by the    number of letters read correctly from 2 meters distance on 100%,    2.5% and 1.25% contrast level Sloan letter/Tumbling-E charts.    Statistical Analysis

The analysis of the total number of confirmed relapses during the studyperiod is based on baseline adjusted Quasi-Likelihood (over-dispersed)Poisson Regression. Using the Poisson regression with the treatmentgroup as a covariate, the ARR of each group was calculated for theintent-to-treat (ITT) cohort as the total number of confirmed relapsesfor all patients in each group divided by the total patient years inthat group. In addition to the treatment group, the following covariateswere included: baseline EDSS score, log of the (prior 2-year number ofrelapses +1) and country or geographical region.

The analysis of the accumulation of physical disability is based onCox's Proportional Hazard model. The analysis of MSFC is based onbaseline-adjusted Analysis of Covariance. The analysis of the secondaryMRI endpoints is based on baseline-adjusted Negative BinomialRegression. To control against type-I error, the secondary endpointswere analyzed only after a significant effect was found for the primaryendpoint. Likewise, the study's overall type-I error was furthercontrolled in the analysis of the secondary endpoints by applying thefollowing gate-keeping approach: both the cumulative number ofnew/enlarging T2 and the cumulative number of GdE lesions at months 12and 24 were tested simultaneously and needed to be statisticallysignificant at p<0.05, or one needed to be significant at p<0.025 if theother endpoint was not statistically significant at the 5% level. If theabove condition was met, the study then proceeded to the analysis of theconfirmed EDSS progression endpoint, if this endpoint was significant at5% level, the analysis was done for the total MSFC z-scores.

Sample size calculations were based on assumptions that the number ofconfirmed relapses in one year reflects an over-dispersed Poissondistribution, and that the expected ARR was 0.65 in untreated subjects,0.6 in the placebo group due to a placebo effect, and 0.45 in thelaquinimod group based on 25% or more reduction in relapse rate comparedto placebo. A simulation study showed that 830 subjects (415 subjectsper arm) would provide approximately 90% power to detect a significantchange in the ARR. To correct for anticipated 20% withdrawal over 24months, the sample was adjusted to 1000 subjects (500 subjects per arm).

The analysis of risk to confirmed disability progression using the ITTcohort was based on Cox's Proportional Hazard model adjusted to baselineEDSS, log of the prior 2 year number of relapses +1 and geographicalregion. The MSFC at month 24 was analyzed using a baseline-adjustedANCOVA (SAS@PROC GLM) with baseline MSFC as 1 degree of freedomcovariate and baseline EDSS score, log of the 2-year prior relapse rate+1 and country or geographical region as additional covariates. Analysesof the MSFC z score at 24 months and the secondary MRI endpointsincluded only patients who did not discontinue from the trial prior tomonth 12 visit.

Analyses of the secondary MRI endpoints of the cumulative number of GdEand new/enlarging T2 lesions at 12 and 24 months involved abaseline-adjusted negative binomial regression with an “offset”employing the log of the relative exposure to adjust forearly-terminated patients. The model included as covariates the numberof enhancing lesions at baseline, and country or geographical region. Inthe case of new/enlarging T2 lesion analysis, the baseline T2 lesionvolume was also added. The MRI secondary endpoints analyses were testedsimultaneously with an overall type I error of 5%, using the Hochberg'sstep-up modification to Bonferroni's method to the two P-values obtainedfrom the analyses of these two endpoints. The analysis of the brainatrophy endpoint involved a baseline-adjusted analysis of covariance(ANCOVA). The covariates were the number of GdE lesions at baseline andthe country or region. The exploratory endpoints were all analyzed at asignificance level of 5%.

Results

The results of the ALLEGRO trial indicated that laquinimod treatmenteffectively reduced annualized relapse rates, slowed the progression ofdisability, reduced brain atrophy, and reduced the development of newlesions. A summary of the study results is presented in Table 2 below:

TABLE 2 Laquinimod, 0.6 mg daily Placebo (n = 550) (n = 556) EffectRelapses Annualized relapse rate^(a) 23% reduction Adjusted means (SE)0.304 (0.022) 0.394-0.395 (0.027) Risk ratio (95% CI) 0.770(0.650-0.911)) Relapse-free during study^(b) 55% increase odds toAdjusted proportions 62.90% 52.24% be relapse free Odds ratio (95% CI)1.550 (1.205-1.994) Risk of first confirmed relapse^(c) Hazard ratio(95% CI) 0.718 95% Confidence Interval 0.595-0.866 Annualized rate ofrelapses 27% reduction requiring hospitalization and/or IV steroids^(d)Adjusted Mean (SE) 0.242 (0.020) 0.334 (0.025) Risk Ratio (95% CI) 0.723(0.606-0.862) Time to 1^(st) confirmed relapse 28% reduction for therisk of 1^(st) confirmed relapse Disability Risk for EDSS progressionconfirmed at 3 months^(e) Hazard Ratio (95% CI) 0.641 (0.452-0.908) Timeto confirmed (3 Ms) 9.8% progressed 14% progressed 36% reduction ofprogression - EDSS risk to progress Patients with no confirmed 496(90.2%) 478 (86.0%) disability progression (%) at LOV^(f) Risk for EDSSprogression confirmed at 6 months^(g) Hazard Ratio (95% CI) 0.516(0.337-0.790) Mean EDSS score at LOV (SE)^(h) 2.68 (0.046) 2.790 (0.046)95% Confidence Interval (2.59-2.77) (2.70-2.88) Median 2.5 2.5 Range 0.0to 8.0 0.0 to 8.5 MSFC Total z scores at 24 months 34% reduction of(including early terminations after risk to progress 12 months)^(i) Mean(95% CI) 0.056 (−0.000 to 0.112) 0.0376 (−0.020 to 0.94) MRI Cumulativenumber of GdE 37% reduction lesions at months 12 and 24^(j) No ofpatients with data 479 464 Mean (SE) 1.332 (0.14) 2.119 (0.22) Median0.00 1.00 Range  0 to 49  0 to 91 Risk ratio (95% CI) 0.629(0.488-0.809) Cumulative number of 30% reduction new/enlarging T2lesions at 12 and 24 months^(k) No. of patients with data 479 464 Mean(SE) 5.032 (0.079) 7.148 (0.075) Risk ratio (95% CI) 0.704 (0.584-0.849)Percent change of brain volume 32.8% reduction  from baseline to month24^(l) No. of patients with data 382 381 Adjusted mean change at month24 −0.871 −1.297 Adjusted mean difference (95% CI) 0.426 (0.267-0.585)BA at month 12 −0.358%  −0.763%  53% reduction T2 volume month 0 7.277.315 T2 volume month 12 8.005 8.441  5% T2 volume month 24 8.111 8.509 5% BL to M 24  11.5%   16% Hypointense T1 volume month 0 2.65 2.65Hypointense T1 volume month 12 2.805 2.894 ~1% Hypointense T1 volumemonth 24 2.829 2.891 ~1% BL to M 24   7%   9% Cumulative new HypointenseT1 1.468 2.002 27% reduction months 12 + 24 ^(a)Baseline adjustedQuasi-likelihood (over-dispersed) Poisson Regression analysis, includingbaseline EDSS score, log of the prior 2-year relapse rate + 1 andcountry or geographical region as covariates. ^(b)Baseline adjustedlogistic regression analysis with covariates baseline EDSS, log of theprior 2-year number of relapse + 1 and country or geographical region.^(c)Cox model regression analysis adjusted to baseline EDSS, log of theprior 2-year number of relapses + 1 and geographical region.^(d)Baseline adjusted Quasi-likelihood (over-dispersed) PoissonRegression analysis, including baseline EDSS score, log of the prior2-year relapse rate + 1 and country or geographical region ascovariates. ^(e)Cox Model regression analysis adjusted to baseline EDSS,log of the prior 2-year number of relapses + 1 and geographical region.^(f)The p-value was calculated using the chi square test. ^(g)Cox Modelregression analysis adjusted to baseline EDSS, log of the prior 2-yearnumber of relapses + 1 and geographical region. ^(h)Baseline adjustedANCOVA with geographical region, EDSS at baseline and the log of theprior 2-year relapse rate + 1 as covariates. ^(i)Baseline adjustedANCOVA with baseline MSFC as 1 degree of freedom covariate and baselineEDSS score, log of the prior 2-year relapse + 1 and country orgeographical region as covariates. ^(j)Baseline-adjusted NegativeBinomial Regression with an offset to adjust for early termination lackof exposure and baseline GdE lesions, and country or geographical regionas covariates. ^(k)Baseline-adjusted Negative Binomial Regression withan offset to adjust for early termination lack of exposure and baselineGdE lesions, and country or geographical region as covariates.^(l)Baseline-adjusted ANCOVA with the number of baseline GdE lesions,and country or geographical region as covariates.

A summary of a post-hoc study results is presented in Table 3 below:

TABLE 3 Placebo Laquinimod Effect ARR 1^(st) year 0.452 0.343 24%reduction No recovery 0.08 0.06 24% reduction Full recovery 0.179 0.15513% reduction ARR for dropouts 0.872 0.640 26% reduction Unconfirmedrelapses 0.112 0.094 17% reduction Relapses requiring 0.114 0.071 38%reduction hospitalization Relapses requiring IV steroids 0.359 0.263 27%reduction ARR by median relapse duration: ≦34 days 0.243 0.153 37%reduction >34 days (n ~100) 0.976 0.964 1.3% reduction  New-T1Hypointense Lesions M 12 1.461 1.074 27% reduction M 24 1.806 1.230 32%reduction T1 Hypointense Lesion free M 12 50.2% 56.3% 28% odds M 2443.1% 52.8% 47% odds BA from M 12 to M 24 −0.561 −0.548 BA for pts withall scans: Change BL to M 12 −0.746 −0.337  60% to M 24 −1.268 −0.855 57% % BVC BL to M 24 MRI free YES −1.078 −0.533 45.5% NO −1.346 −1.00165.5% GdE counts M 12 1.142 0.731 36% reduction M 24 0.793 0.482 39%reduction GdE lesion free M 12 59.9%  69% 49% odds M 24 62.8% 74.5% 72%odds GdE volume M 12 1.109 1.058  4.5% M 24 1.091 1.045  4.7% T2 lesionfree M 12 24.2% 30.8% 39% odds M 24 15.4% 20.3% 40% odds New T2 lesion#M 12 4.23 2.81 33.5% M 24 6.50 4.45 31.5% % BV change M 24 GdE = 0−1.218 −0.859 30% reduction GdE > 0 −1.380 −0.881 37% reduction Cum # T1GdE by previous medications: naïve 1.937 1.135 42% reduction not naive2.562 1.746 32% reduction Cum New T2 by previous medications: naïve7.403 4.967 33% reduction not naive 6.661 5.075 24% reduction T1hypointense by previous medications: naïve 2.189 1.585 28% reduction notnaive 1.627 1.217 25% reduction % BV change by previous medications:naïve −1.327 −0.82 38% reduction not naive −1.241 −0.954 23% reductionTime to confirmed (3 Ms) 14% progressed 9.8% progressed 36% reduction ofprogression - EDSS risk to progress MSFC at M 24 0.037 0.056 34%reduction of risk to progress * Recover refers to EDSS before and afterattackOral Laquinimod Reduced Severe Relapses and Slowed DisabilityProgressionRelapse Endpoints:

The ARR during the 24-month treatment period was significantly reducedin the laquinimod patients compared to placebo patients (0.304±0.022 vs0.395±0.027, p=0.0024, Table 2). This result was robust and consistentin all analysis sets. Other relapse-related measures, such as time tofirst relapse and relapse free rates were also positively changedfollowing laquinimod treatment as compared to placebo. The percentage ofrelapse-free patients was 62.9% for laquinimod and 52.24% for placebosubjects (p=0.0006, Table 2), corresponding to an increase of 55% in theodds to be relapse-free. The time to the first relapse was prolonged forlaquinimod patients compared to placebo participants (increase of 28.2%in the time to first relapse, p=0.0005) and the risk for relapse wassignificantly reduced. The annualized rate of relapses requiringhospitalizations and/or intravenous steroid treatment, an exploratoryendpoint of the study, was found to be significantly lower for patientstreated with laquinimod compared with those in the placebo arm(p=0.0003). The annualized rate of relapses requiring IV steroids was27% lower for laquinimod patients (0.263 vs 0.359, p<0.0001). Theannualized rate of relapses requiring hospitalization was 0.071 vs.0.114, p<0.0001, a 38% reduction for laquinimod patients. Based on thereduction in relapse rate, it can be said that laquinimod reduces thelikelihood that a relapsing-remitting multiple sclerosis human patientwould experience a confirmed relapse within a predetermined time period.

Disability Endpoints:

The ALLEGRO results clearly show that laquinimod reduced both relapseseverity and accumulation of disability in patients with RRMS.

In this study, secondary endpoint on disability included the risk todisability progression (change in EDSS score ≧1.0 points if baselineEDSS 0-5.0 or change ≧0.5 point if baseline EDSS≧5.5) confirmed at 3months. Predefined additional disability endpoints included the risk ofdisability progression confirmed at 6 months, the risk of disabilityprogression at last observed value (LOV), and the proportion of patientswith confirmed disability progression sustained for 3 months.

EDSS scores confirmed after 3 months was significantly decreased by 36%for laquinimod patients (hazard ratio=0.641, 95% CI: 0.452-0.908,p=0.0122; Table 2). There was also a 48% decrease in the risk for 6month confirmed EDSS progression (HR=0.516, 95% CI: 0.337-0.790,p=0.0023). This observation was reinforced by the 35% reduction in riskof confirmed progression using the more stringent approach requiring thepersistence of EDSS change at the last available visit (hazardratio=0.656, p=0.036). The proportion of patients with confirmed EDSSprogression after 24 months was 9.8% for laquinimod and 14.0% forplacebo (p=0.038; Table 2). A post-hoc subgroup analysis indicated that33/54 (61.1%) laquinimod and 53/78 (67.9%) placebo patients whoprogressed also had a relapse during the study. There was little overallchange in the MSFC scores from baseline to month 24 and no significantdifferences were found between the adjusted mean total MSFC z scores forlaquinimod and placebo treated patients at 24 months (z scores=0.056 and0.037, respectively, p=0.5893). The significant decrease in time to andrisk for confirmed progression disease activity, as measured by, e.g.,the EDSS score of the patient, is suggestive of laquinimod having aneuroprotective property.

This clinical finding was supported by MRI measures (defined asexploratory endpoints), such as progression of brain atrophy andT1-hypointense lesion counts. The MRI results are discussed in moredetail below.

Oral Laquinimod Reduced MRI Markers of Neurodegeneration

Secondary endpoints of the ALLEGRO trial included disease activity asmeasured by MRI, including counts of Gadolinium enhancing T1 lesions andnew-T2 hyperintense lesions. The study evaluated laquinimod's effects ona variety of conventional (T1 hypointensity and brain volume) andadvanced (magnetization transfer (MT) imaging and proton magneticresonance spectroscopy (¹H-MRS)) MRI measures of tissue damage.Conventional MRI scans for new T1 hypointense lesions, and brain volumeusing SIENA were performed at baseline, 12 and 24 months. At 10 sites(n=93), MT MRI was obtained at the three time points and at 6 sites(n=39), NAA/Cr ratios from ¹H-MRS were obtained from a volume ofinterest (VOI) placed in the central white matter at baseline and laststudy visit.

Laquinimod was found to reduce the mean cumulative number of GdE lesionscompared to placebo by 37% (risk ratio=0.629, p=0.0003). The meancumulative number of new/enlarged T2 lesions at months 12 and 24 wasalso reduced in laquinimod patients by 30% (risk ratio=0.704, p=0.0002).The mean cumulative number (at month 12 and 24−termination/earlytermination after month 12) of new hypointense T1 lesions was reduced by26.7% in the laquinimod group compared to placebo group (1.47 vs 2.00respectively, p=0.0039). Change in mean MTR whole brain from baseline tolast observed value (LOV) decreased for placebo patients (n=40) by−0.438 and on the contrary remained stable for laquinimod patients(+0.045 change, n=44), representing a difference of 0.483 (p=0.0180). Inthe same direction, the average MTR of T2 visible lesions was decreasedby −0.335 for placebo patients (n=40) and stable for laquinimod patients(−0.005 change, n=43), representing a difference of 0.330 (p=0.1007).The adjusted mean change in NAA/Cr from baseline to month 24 was 0.087for laquinimod (n=12) and −0.145 for placebo (n=15) patients (p=0.1738).

The percent change in brain volume progressed at a greater rate in theplacebo group compared to the laquinimod group from baseline to 12months, −0.763 vs. −0.358 and from baseline to 24 months −1.297 vs−0.871, (adjusted mean difference=0.426, p<0.0001) respectively,reflecting a 51.7% and 32.8% reduction in brain atrophy by laquinimodtreatment.

The MRI data show that laquinimod had a clear effect in preventingirreversible tissue loss and is consistent with its impact on disabilityprogression.

Laquinimod Maintained or Improved Fatigue and Functional Status ofPatients

As patient-reported exploratory endpoints, fatigue was assessed usingthe Modified Fatigue Impact Scale (MFIS) and functional status using theshort-form (SF)-36 general health survey. Both measures were completedat the baseline, 6, 12, 18 and 24 month clinic visits and were analyzedusing an ANCOVA adjusted for baseline EDSS, 2-year prior relapse rateand country/region. A summary of the quality of life (QOL) results ispresented in Table 4 below:

TABLE 4 Exploratory Placebo Laquinimod Effect p MFIS 34.4 31.9 −2.530.004 Subject-Reported Fatigue -the Modified Fatigue Impact Scale Whilethe mean total MFIS score for those treated with laquinimod 0.6 mg atMonth 24 remained stable, the mean total MFIS score for those treatedwith placebo had increased reflecting increased functional disabilitydue to fatigue. From the patients' perspectives, laquinimod 0.6 mg was,on average, associated with less functional disability due to fatiguethan placebo at Month 24 SF36 - SFMHD −2.314 −0.47 1.848 0.001 Mentalcomponent summary The MCS score at Month 24 for those treated withlaquinimod 0.6 mg remained stable while the MCS score for those treatedwith placebo declined. The patients' self-assessment of their mentalhealth status with laquinimod 0.6 mg was, on average, better than withplacebo at Month 24 SF36 - SFPHD −1.169 −0.519 0.65 0.1354 Physicalcomponent summary The PCS score at Month 24 for those treated withlaquinimod 0.6 mg remained stable while the PCS score for those treatedwith placebo declined. The patients' self-assessment of their mentalhealth status with laquinimod 0.6 mg was, on average, better than withplacebo at Month 24 EQ5D 68.6 71.0 −2.366 0.0267 General Health Statusby the Euroqol Questionnaire was assessed with the 5 dimension EQ-5Ddescriptive profile (Mobility, Self Care, Usual Activities, Pain orDiscomfort, and Anxiety or Depression) The results of the individualEQ-5D dimensions analyses show that those treated with laquinimod 0.6 mgmaintained their health status at Month 24 while those treated withplacebo reported a decline, on average, in health status. Dimensionswith the most variation in health status between treatments at Month 24were Mobility, Self-Care, and Anxiety or Depression Mobility 1.4970.0181 Self care 2.251 0.0337 Usual activities 1.129 0.4051 Paindiscomfort 1.036 0.8024 Anxiety or Depression 1.425 0.0113

At baseline fatigue was more than twice the published mean scores forhealthy individuals: 31.1 (0.79) for laquinimod and 30.6 (0.73) forplacebo patients. Fatigue worsened in placebo patients during the trialwith an adjusted mean score at 24 months of 34.4 (0.71) compared tothose treated with laquinimod of 31.9 (0.71), a treatment effect forlaquinimod of −2.53, (p=0.004). Changes in adjusted mean MFIS subscalescores from baseline showed a significant improvement in the laquinimodgroup: cognitive at 24 months (p=0.05); physical at 24 months (p=0.02);and psychosocial at 12 months (p=0.02). For the SF-36, the adjustedtreatment effect difference between laquinimod and placebo on the mentalcomponent summary was 1.68 (p=0.004), with the subscales for vitality,social functioning and role emotional contributing to this effect.Although the physical component summary (PCS) remained stable forlaquinimod over 24 months and the PCS for the placebo group declined,the difference did not reach statistical significance (p=0.13). Two ofthe PCS subscales: physical functioning (p=0.016) and role physical(p=0.010) showed improvement over 24 months with laquinimod versusplacebo.

The results of the ALLEGRO trial suggest that fatigue and functionalstatus of patients treated with laquinimod was maintained or improvedcompared to that of placebo patients and that these effects support therobust clinical effects seen on disability progression and relapse rate.

Safety and Tolerability

No deaths occurred in the laquinimod group and 3 deaths occurred in theplacebo group (injury, suicide and complications related to pneumonia).A total of 122 serious adverse events (SAEs) were reported forlaquinimod and 90 for placebo patients. A higher incidence ofappendicitis was reported in laquinimod treated patients (5 cases versus1 in the placebo group). In all cases appendectomy was performed withoutadditional complications and patients continued with study treatment.Overall, there were 14 cases of neoplasms evenly distributed across botharms (8 in laquinimod and 6 in placebo groups) with a large variabilityin the type of cancers.

There were 3309 and 2965 adverse events in the laquinimod and placeboarms with 87% and 81% of patients reporting 1 or more events,respectively. The 3 most common adverse events in the laquinimod groupcompared to placebo (excluding liver enzyme elevations discussed below)were abdominal pain (n=32, 5.8% vs. n=16, 2.9%), back pain (n=90, 16.4%vs. n=50, 9%) and cough (n=41, 7.5% vs n=25, 4.5%). These adverse eventswere rarely associated with study discontinuation, (3% of laquinimod and1% of placebo patients). More laquinimod patients (n=27, 4.9%; vs n=11,2.0% in placebo) showed a shift to abnormal values in the liveraminotransferases, specifically, alanine aminotransferase (ALT) ≧3 timesupper limit normal (3×ULN) and <5×ULN during the study. Treatmentdiscontinuation occurred in 7 laquinimod and 2 placebo patients due toALT≧3 and <5×ULN. By contrast, ALT elevations ≧5×ULN occurred equallyoften in both groups (8 vs. 8) and led to equal rates ofdiscontinuation. Elevations up to 5×ULN usually occurred within thefirst 6 months and all were reversible either without studydiscontinuation or within 2 months of withdrawal. There were no cases ofliver failure and no cases of liver insufficiency as evidenced byconcomitant elevations of bilirubin or coagulation tests (Hy's Law)(Temple, 2006).

Discussion

Laquinimod is a promising a treatment for relapsing remitting MS, basedon its effects on the accumulation of tissue damage, as indicated byconsistent effects on clinical measures of disability and MRI measuresof disease burden, its oral route of administration and its safetyprofile.

Laquinimod had a significant effect on inflammatory activity whichcharacterizes the relapsing remitting course of MS. The effect was seenin the reduction of relapse rate, the primary end point of the study, aswell as reduction of active MRI lesions. The reduction of relapse ratewas highly consistent with effects seen on MRI measures of diseaseactivity, which has not always been the case for other disease modifyingtreatments (DMTs) (The IFNB Multiple Sclerosis Study Group, 1993;Jacobs, 1996; PRISMS Study Group, 1998). Moreover, laquinimod had asignificant effect on confirmed disability progression, which isconsidered a core outcome measure in MS. Although the overall proportionof patients with disease progression in the placebo arm was modest, thereduction in the laquinimod arm was a real phenomenon, as the effect wasconfirmed by sensitivity analyses including the more stringent criteriaof disability progression, such as the 6 month confirmation period andthe persistence of the EDSS change at the last available visit. Subgroupanalyses showed that disability progression in both groups waspredominantly due to attacks, which were less severe and followed by abetter recovery in laquinimod treated patients. This is in line withpreclinical studies which show a moderate effect of the drug on lesionnumbers and a pronounced effect on the axonal damage inside the lesions(Thöne, 2011). The peculiar property of laquinimod to reduce theaccumulation of irreversible tissue damage in MS is further supported bythe significant decrease in the progression of brain tissue loss whichwas similar in magnitude to what has been reported previously for otherDMTs (Kappos, 2010; Rudick, 1999; Sormani, 2004; Miller, 2007) that havea larger impact on inflammatory activity. No significant effects wereobserved for MSFC, likely due to the very small mean longitudinalchanges seen in both arms. A practice effect may have obscuredlongitudinal changes of the MSFC components as there was an improvementof the MSFC scores in the placebo arm, whereas other trials have shown adeterioration (Kappos, 2010; Cohen, 2010).

The ALLEGRO study further confirmed the very good safety profile oflaquinimod demonstrated in phase II. There were no increased rates ofserious adverse events in the trial. One safety signal was liver enzymeelevations which occurred two times more frequently in the laquinimodtreated arm. These elevations occurred mostly in the first treatmentperiod and were usually modest; values exceeding 5×ULN occurred equallyoften in the laquinimod and placebo arms. The liver enzyme elevationswere always reversible even in patients with ≧3×ULN and were neverassociated with clinical, imaging or laboratory signs of liverinsufficiency or failure. One potential signal of a tolerability issuewas abdominal pain which occurred more frequently and resulted intreatment discontinuation more frequently in the laquinimod arm. As withALT elevations, abdominal pain was reported in the early phases oftreatment exposure. It is worth noting that the safety concernspreviously seen with roquinimex (Noseworthy, 2000) such as serositis,cardiovascular events and thrombosis did not emerge as signals in theALLEGRO study.

The results seen in this study are unique. Data obtained from pivotalstudies of other drugs with proven effect on progression of disabilityin a placebo-controlled setting, shows a magnitude of effect which iscorrelated with the effect on relapses. With all other drugs to date,the effect on progression of disability has been equal or lower than theeffect on the ARR.

In comparison, the results of this study show that the effect oflaquinimod on the progression of disability, which is a more importantlong-term measure of Multiple Sclerosis is considerably higher thanother drugs, suggesting that the effect of laquinimod is not necessarilya derivative of its anti-inflammatory properties but also composed ofpure neuroprotection, as seen in animal models. Therefore, this studyshows that laquinimod is not only effective for treating MS by the wayof its anti-inflammatory properties, it also provides neuroprotection toprotect neural cells against neuronal injury or degeneration.

Conclusion

This phase III study supports laquinimod as a new option for thetreatment of RRMS with reductions in relapses and disability progressionand no safety signals other than a transient elevation of liver enzymes.No apparent increases was seen in infections or malignancies. Treatmentwith laquinimod was associated with reduction of annualized relapse ratefrom 0.395±0.027 for placebo patients to 0.304±0.022 for laquinimodpatients (p=0.0024) and with a lower risk of confirmed EDSS progression(Hazard ratio=0.641, 95% CI: 0.452-0.908, p=0.0122). Mean cumulativenumber of GdE and new/enlarging T2 lesions were lower for laquinimod(p=0.0003 and p=0.0002), and the rate of brain volume reduction wasreduced (p<0.0001) at month 24.

Example 2 Clinical Trial (Phase III)—Benefit-Risk Assessment of Avonex®and Laquinimod

A multinational, multicenter, randomized, parallel-group, clinical trialis performed in subjects with RRMS (“BRAVO”). BRAVO was conducted toassess the efficacy, safety and tolerability of laquinimod over placeboin a double-blinded and rater-blinded design and of a reference arm ofInterferon β-1a (Avonex®). The study was also conducted to perform acomparative benefit/risk assessment between oral laquinimod andinjectable Interferon β-1a (Avonex®).

The primary objective of the study was to assess the efficacy of 0.6 mgdaily dose of laquinimod in subjects with RRMS as measured by the numberof confirmed relapses during the treatment period. Secondary objectivesof the study included assessing the effect of 0.6 mg daily dose oflaquinimod on the accumulation of disability, as assessed by the MSFCscore at the end of the treatment period; assessing the effect of 0.6 mgdaily dose of laquinimod on the development of brain atrophy as definedby the percent brain volume change from baseline at the end of thetreatment period; and assessing the effect of 0.6 mg daily dose oflaquinimod on the accumulation of physical disability as measured by thetime to confirmed progression of EDSS during the treatment period.

The 2006 EMEA Guidelines for MS clinical trials states that activecontrol parallel group trials comparing the new treatment to an alreadyapproved treatment are needed in order to give the comparativebenefit/risk ratio of the new treatment, at least in those treatmentintended to prevent relapses. Three-arm studies with placebo, testproduct and active control are a preferred design.

Avonex® (Interferon beta-1a) is a 166-amino acid glycoprotein producedby recombinant DNA technology using genetically engineered ChineseHamster ovary cells into which the human interferon beta gene has beenintroduced. The amino acid sequence of Avonex® is identical to that ofnatural human interferon beta.

Avonex® is a marketed drug indicated for the treatment of patients withrelapsing forms of MS to slow the accumulation of physical disabilityand decrease the frequency of clinical exacerbations. Patients withmultiple sclerosis in whom efficacy has been demonstrated includepatients who have experienced a first clinical episode and have MRIfeatures consistent with MS.

The recommended dosage of Avonex® is 30 mcg injected intramuscularlyonce a week.

Study Duration

Screening phase: 1 month or up to 30 days.

Treatment phase: 24 months of once-daily oral administration oflaquinimod 0.6 mg, matching oral placebo or once-weekly intramuscularadministration of Interferon β-1a (Avonex®) 30 mcg.

Subjects successfully completing the study are offered the opportunityto enter into a 1-year open-label extension in which laquinimod 0.6 mg/dare administered.

A month is defined as 30±4 days in this study.

Number of Subjects

Approximately 1200 subjects.

Prior to the end of the recruitment period, a blinded relapse rate andsample size reassessment is performed. Based on the newly estimatedrelapse rate of the population, the sample size may be increased.

Dropouts are not replaced.

Study Design

Treatment Arms

Eligible subjects are randomized in a 1:1:1 ratio (oral laquinimod:oralplacebo:Avonex®) and assigned to one of the following three treatmentarms:

-   1. Laquinimod 0.6 mg per os once daily (400 subjects).-   2. Matching placebo (for laquinimod) per os once daily (400    subjects).-   3. Interferon β-1a (Avonex®) 30 mcg intramuscular injection once    weekly (400 subjects).    Route and Dosage Form

0.6 mg arm: one capsule containing 0.6 mg laquinimod is administeredorally once daily. The 0.6 mg laquinimod capsule contains 0.6 mg ofLaquinimod Acid per capsule with meglumine.

The 0.6 mg laquinimod capsule is manufactured according to the methoddisclosed in PCT International Application Publication No.WO/2007/146248, published Dec. 21, 2007 (see, page 10, line 5 to page11, line 3).

Matching placebo for laquinimod arm: one capsule is administered oncedaily.

Blinding

Subjects on oral treatment are managed in a double-blind manner.Subjects assigned to injectable treatment with Avonex® and theirTreating Neurologist/Physician are unblinded to the treatmentassignment, but assessed neurologically by an ExaminingNeurologist/Physician in a blinded manner (potential IM injection sitesare covered).

Assessments at Specified Time Points

During the treatment phase, subjects are evaluated at study sites for atotal of 12 scheduled visits at months: −1 (screening), 0 (baseline), 1,2, 3, 6, 9, 12, 15, 18, 21 and 24 (termination/early discontinuation).

During the study, the following assessments are performed (regardless ofthe treatment assignment) at the specified time points:

-   1. Vital signs (temperature, pulse, blood pressure) are measured at    each study visit.-   2. A physical examination is performed at months −1 (screening), 0    (baseline) 1, 3, 6, 12, 18 and 24 (termination/early    discontinuation).-   3. The following safety clinical laboratory tests are performed:    -   a. Hematology and Complete blood count (CBC) with        differential—at all scheduled visits. A reticulocyte count is        added to the CBC at months 0 (baseline) and 24        (termination/early discontinuation) as well as in occasions of        significant decrease in hemoglobin.    -   b. Serum chemistry (including electrolytes, liver enzymes,        direct and total bilirubin, CPK and pancreatic amylase), and        urinalysis—at all scheduled visits.    -   c. Serum TSH, T3 and Free T4 are measured at months 0        (baseline), 6, 12, 18 and 24 (termination/early        discontinuation).    -   d. A rapid urine β-hCG test is performed in women of        child-bearing potential at baseline (month 0; all subjects) and        at each scheduled study visit thereafter (at site; only subjects        assigned to oral treatment).    -   e. β-hCG in women of child-bearing potential are performed at        each study visit.    -   f. Starting after visit Month 3 a rapid urine β-hCG test is        performed in women of child-bearing potential (only those        assigned to oral treatment) every 28 (±2) days. The subject is        contacted by telephone with 72 hours after the test is scheduled        to be performed and asked specific questions regarding the test.        In case of suspected pregnancy (positive urine β-hCG test        result), the caller makes sure that the study drug has been        discontinued and the subject is instructed to arrive to the site        as soon as possible with all study drugs.-   4. Markers of inflammation (serum conventional C-reactive protein    and fibrinogen) are measured at all scheduled visits.-   5. Serum samples are collected for evaluation of immunological    parameters and response to treatment with either laquinimod or    Avonex®, as well as further investigation of the potential    mechanisms of action of laquinimod or for the detection of    infectious agents. These samples are collected at months 0, 12 and    24.-   6. During the first 3 months of the study, periodical phone calls    are placed by the site personnel every two weeks and fourteen (±2)    days post month 1 and month 2 visits, the patient is asked questions    relating to signs or symptoms suggestive of vascular thrombosis is    presented to the subject and a list of predefined questions relating    to signs/symptoms suggestive of vascular thrombosis is presented to    the subject. In case of suspected thrombotic event, the subject is    requested to arrive at the site immediately for further evaluation.    Fourteen (±2) days post month 1 and month 2 visits, the patient is    asked questions relating to signs or symptoms suggestive of vascular    thrombosis is presented to the subject.-   7. ECG is performed at months −1 (screening; additional recording,    up to 30 minutes apart are performed if QTc is >450 msec), 0    (baseline; three recordings, 15 minute apart), 1, 2, 3, 6, 12, 18    and 24 (termination/early discontinuation).-   8. Chest X-ray is performed at month −1 (screening) (if not    performed within 6 months prior to screening visit).-   9. Adverse Events (AEs) are monitored throughout the study and    recorded.-   10. Concomitant medications are monitored throughout the study.-   11. Neurological evaluations, including Neurostatus [Functional    Systems (FS), Expanded Disability Status Scale (EDSS; Converted    scale), Ambulation Index (AI)] and Timed-25 foot walk test are    performed at months −1 (screening), 0 (baseline) and every 3 months    thereafter, until termination/early discontinuation. (At screening    visit, the Timed-25 foot walk test is performed 3 times, for    practicing purposes, as a part of the MSFC).-   12. MS Functional Composite (MSFC) is assessed at months −1    (screening) (three practices for training purposes only), 0    (baseline), 6, 12, 18 and 24 (termination/early discontinuation).-   13. The general health status is assessed by the EuroQoL (EQ5D)    questionnaire at months 0 (baseline) and 24 (termination/early    discontinuation).-   14. The general health status and quality of life parameters are    assessed by the Short-Form general health survey (SF-36)    subject-reported questionnaire at month 0 (baseline) and every 6    months thereafter until termination/early discontinuation,    inclusive.-   15. Subject-reported fatigue is assessed by the Modified Fatigue    Impact Scale (MFIS) at months 0 (baseline), 2, 6, 12, 18 and 24    (termination/early discontinuation).-   16. All subjects undergo 3 MRI scans at months 0 (13-7 days prior to    baseline visit), 12 and 24 (termination/early discontinuation).    Subjects undergo MRI scan before and after Gadolinium administration    (month 12).-   17. All subjects undergo 5 assessment of binocular low-contrast    visual acuity using the 1.25%, 2.5% and 100% contrast level charts    [Sloan letter or Tumbling-E] in each assessment, at months 0    (baseline), 6, 12, 18 and 24 (termination/early discontinuation).-   18. Blood test for Factor V Leiden mutation (FVLM) is performed at    screening visit.-   19. Serologies for Hepatitis B and C viruses are performed at    screening visit.-   20. Relapses are confirmed/monitored/evaluated throughout the study.    Since the “in study” relapse definition must be supported by an    objective neurological evaluation, a neurological deficit must    sustain long enough to eliminate pseudo-relapses. Therefore, in    Bravo, a confirmed relapse is the appearance of one or more new    neurological abnormalities or the reappearance of one or more    previously observed neurological abnormalities wherein the change in    clinical state lasts at least 48 hours and is immediately preceded    by an improving neurological state of at least thirty (30) days from    onset of previous relapse.-   21. The allowed treatment for a relapse is intravenous    methylprednisolone 1 gr/day for up to 5 consecutive days.-   22. Assessment of the effect of general health and symptom severity    on work, using the work productivity and activities    impairment—General Health (WPAI-GH) questionnaire (months 3, 6, 9,    12, 15, 18 and 21) (this assessment is performed in all subjects    from US sites only).-   23. The sequence of assessments performed during the visits is as    follows:    -   a. Short-Form general health survey (SF-36) subject-reported        questionnaire (months 6, 12 and 18)    -   b. Modified Fatigue Impact Scale (MFIS) (months 2, 6, 12 and 18)    -   c. The work productivity and activities impairment General        Health (WPAIGH) questionnaire (applicable only to US sites,        months 3, 6, 9, 12, 15, 18 and 21)    -   d. The 9-Hole Peg and PASAT components of the MSFC (Timed 25        Foot walk may be performed later) (months 6, 12 and 18)-   24. The rest of the visit activities, as described above-   25. For subjects who are assigned to oral treatment, the last dose    of study drug is taken one day prior to the Termination visit day.-   26. For subjects who are assigned to injections, the study drug    (Avonex®) is not administered on Termination visit day.    Safety Parameters—Adverse Events

Adverse events are recorded from when a subject has signed the InformedConsent Form and throughout the study, until 30 days following thetermination visit.

Safety Parameters—Safety Laboratory Evaluations

The following tests are performed:

-   1. Serum Chemistry: Glucose, Creatinine, Bilirubin (direct and    total), Urea, AST (SGOT), ALT (SGPT), GGT, Pancreatic Amylase, Lipid    profile (once in the study either at screening or baseline visits;    12-hours-fasting is mandatory: Total cholesterol, LDL cholesterol,    HDL cholesterol and triglycerides), Total Protein Albumin, CRP (C    reactive protein, conventional assay), Alkaline Phosphatase, CPK,    T3, Free T4, and TSH [only at months 0 (baseline), 6, 12, 18 and 24    (termination/early discontinuation)].-   2. Electrolytes: Sodium, Potassium, Calcium, and Phosphorous.-   3. Coagulation: Fibrinogen and INR (performed in a local laboratory)-   4. Hematology: Hemoglobin, MCH, MCV, MCHC, Hematocrit, Red Blood    Cells count (RBC), White Blood Cells count+differential, Platelet    count, and a reticulocyte count is added to the CBC at months 0    (baseline) and 24 (termination/early discontinuation visit), and in    any case of a ≧2 g/dL decrease in hemoglobin, as compared to    baseline level. In such cases, measurement of reticulocyte count    continues with each CBC test until the difference between hemoglobin    value and baseline hemoglobin is <2 g/dL.-   5. Factor V Leiden Mutation: This sample (for this mutation only) is    collected at screening visit and stored frozen in the central    laboratory. This sample may be analyzed upon request of the DMC at    any time during the study. If, from any reason, the subject is a    screening failure, this sample is destroyed.-   6. Pregnancy tests-   7. Urinalysis: glucose, ketones, erythrocytes, leukocytes and    protein-   8. Serology (to be performed only for a confirmed abnormality of    liver enzymes): anti-Hepatitis A IgM antibodies, hepatitis B Surface    antigen, anti-Hepatitis B Core IgM antibodies, anti-Hepatitis C IgG    antibodies, anti-nuclear antibodies, anti-Smooth Muscle (Sm)    antibodies, and anti-Liver-Kidney Microsomes (LKM)-1 antibodies    Safety and Pharmacovigilance

A new condition or the worsening of a pre-existing condition isconsidered an AE. Stable chronic conditions that are present prior tostudy entry and does not worsen during the study are not considered AEs.

The date of onset, a description of the AE, severity, seriousness,action taken, relationship to the study drug, outcome of the event anddate of resolution is recorded.

Ancillary Studies

Pharmacogenetic (PGt) assessment: Upon the approval of this ancillarystudy by EC/IRB, blood samples for PGt parameters are collected from allsubjects who signed the informed consent form at month 0 (baseline).

Relationship between PGt and response to laquinimod or to Avonex® interms of clinical, MRI and safety parameters is assessed in all sites.

The effect of general health and symptom severity on work is assessed bythe work productivity and activities impairment-General Health (WPAI-GH)questionnaire at month 0 (baseline) and every 3 months thereafter, untilmonth 24 (termination/early discontinuation) visit (this assessment isperformed in all subjects from the U.S. sites only).

Inclusion/Exclusion Criteria

Inclusion Criteria

-   1. Subjects must have a confirmed and documented MS diagnosis as    defined by the Revised McDonald Criteria [Ann Neurol    2005:58:840-846], with a relapsing-remitting disease course.-   2. Subjects must be ambulatory with Converted EDSS score of 0-5.5 in    both screening and baseline visits.-   3. Subjects must be in a stable neurological condition and free of    corticosteroid treatment [intravenous (IV), intramuscular (IM) and    or per os (PO)] 30 days prior to screening (month −1) and between    screening (month −1) and baseline (month 0) visits.-   4 Subjects must have had experienced one of the following:    -   a. At least one documented relapse in the 12 months prior to        screening, or    -   b. At least two documented relapses in the 24 months prior to        screening, or    -   c. One documented relapse between 12 and 24 months prior to        screening with at least one documented T1-Gd enhancing lesion in        an MRI performed within 12 months prior to screening.-   5. Subjects must be between 18 and 55 years of age, inclusive.-   6. Women of child-bearing potential must practice an acceptable    method of birth control. Acceptable methods of birth control in this    study include: surgical sterilization, intrauterine devices, oral    contraceptive, contraceptive patch, long-acting injectable    contraceptive, partner's vasectomy or a double-barrier method    (condom or diaphragm with spermicide).-   7. Subjects must be able to sign and date a written informed consent    prior to entering the study.-   8. Subjects must be willing and able to comply with the protocol    requirements for the duration of the study.    Exclusion Criteria-   1. An onset of relapse or any treatment with corticosteroid    (intravenous [IV], intramuscular [IM] and/or per os [PO]) or ACTH    between month −1 (screening) and 0 (baseline).-   2. Subjects with progressive forms of MS.-   3. Use of experimental or investigational drugs, and/or    participation in drug clinical studies within the 6 months prior to    screening.-   4. Use of immunosuppressive (including Mitoxantrone (Novantrone®))    or cytotoxic agents within 6 months prior to the screening visit.-   5. Previous use of either of the following: natalizumab (Tysabri®),    cladribine, laquinimod, Interferon beta-1a (Avonex® or Rebif®),    Interferon beta beta-1b (Betaseron®/Betaferon®) or any other    experimental Interferon-beta for MS.-   6. Previous treatment with glatiramer acetate (Copaxone®) or IVIG    within 2 months prior to screening visit.-   7. Chronic (more than 30 consecutive days) systemic (IV, PO or IM)    corticosteroid treatment within 2 months prior to screening visit.-   8. Previous total body irradiation or total lymphoid irradiation.-   9. Previous stem-cell treatment, autologous bone marrow    transplantation or allogenic bone marrow transplantation.-   10. A known history of tuberculosis.-   11. Acute infection within 2 weeks prior to baseline visit.-   12. Major trauma or surgery within 2 weeks prior to baseline visit.-   13. Known human immunodeficiency virus (HIV) positive status.-   14. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline    visit.-   15. Use of amiodarone within 2 years prior to screening visit.-   16. Pregnancy or breastfeeding.-   17. A ≧3×ULN serum elevation of either ALT or AST at screening.-   18. Serum direct bilirubin which is ≧2×ULN at screening.-   19. A QTc interval which is >450 msec (according machine output),    obtained from:    -   a. Two ECG recordings at screening visit, or    -   b. The mean value calculated from 3 baseline ECG recordings.-   20. Subjects with a clinically significant or unstable medical or    surgical condition that, in the Investigator's opinion, would    preclude safe and complete study participation, as determined by    medical history, physical examination, ECG, laboratory tests or    chest or chest X-ray. Such conditions may include:    -   a. A cardiovascular or pulmonary disorder that cannot be        well-controlled by standard treatment permitted by the study        protocol.    -   b. A gastrointestinal disorder that may affect the absorption of        study medication.    -   c. Renal, metabolic or hematological diseases.    -   d. Thyroid disease: a subject with hyperthyroidism is not        permitted to participate in the study. A subject with        hypothyroidism may be permitted to participate in the study        provided that he/she is clinically euthyroid and considered        stable.    -   e. Liver disease, such as cirrhosis.    -   f. A family history of Long-QT syndrome.    -   g. A history of drug and/or alcohol abuse.    -   h. A current major psychiatric disorder, including schizophrenia        or severe depression, with or without suicidal ideation.    -   i. A history of seizure disorder, with the last convulsion        occurring within 12 months prior to screening visit.-   21. A known history of sensitivity to Gadolinium.-   22. Inability to successfully undergo MRI scanning.-   23. A known drug hypersensitivity that would preclude administration    of laquinimod, such as hypersensitivity to: mannitol, meglumine or    sodium stearyl fumarate.-   24. A known history of hypersensitivity to natural or recombinant    interferon beta, human albumin, or any other component of the    formulation of Avonex®.

Additional disallowed concomitant medications/therapies: interferons,glatiramer acetate) (Copaxone®), Natalizumab (Tysabri®), inhibitors ofCYP3A4, Mitoxantrone (Novantrone®), oral steroids, parenteral steroids(except as given as allowed for treatment of an acute relapse),chemotherapeutic agents, 4-amino pyridine or 3,4 diaminopyridine, IVImmunoglobulin (Ig) and any other experimental agents, and otherImmunosuppressive or immunomodulating agents.

A partial list of CYP3A4 inhibitors (disallowed 2 weeks prior and duringtreatment period) is listed below:

Cardiac drugs/antiarrhythmic agents such as amiodaronec, diltazem,nifedipine, verapamil, or mibefradil; Antimicrobial agents such asErythromycin, Clarithromycin, Troleandomycin, Telithromycin,Fluconazole, Itraconazole, Ketoconazole, Miconazole, or Voriconazole;HIV drugs such as Delavirdine or Protease Inhibitors, such as indinavir,ritonavir and others; Antidepressants such as fluoxetine, fluvoxamine,or nefazodone; and other CYP3A4 inhibitors such as isoniazid, quinine,cimetidine, zileuton, or aprepitant.

Statistical Considerations

The sample size considerations for the study are based on the followingassumptions:

-   1. An individual subject's number of confirmed relapses during a one    year period reflects a Poisson process with an individual rate of    λi, and this individual subject rates λi are exponentially    distributed with mean 1/θ, where θ is the population's annualized    relapse rate. This approach models the total number of confirmed    relapses as an Over Dispersed Poisson distribution.-   2. The expected annualized relapse rate in an untreated patient    population is θ=0.65 relapses per year.-   3. In the placebo treatment group, the expected annualized relapse    rate is θ=0.6 relapses per year, due to a placebo effect.-   4. Treatment with laquinimod reduces the patient population    annualized relapse rate by 25% or more when compared to the placebo    group. That is, the expected annualized relapse rate of the    laquinimod treated population is θ=0.45 relapses per year or less.

A simulation study accounting for the above underlying assumptions usedthe Quasi-likelihood (over-dispersed) Poisson regression (SAS® PROCGENMOD), revealed that a total of 666 subjects (333 subjects per arm)provides approximately 80% power to detect a statistically significantreduction of 25% in the total number of confirmed relapses between theplacebo group and the laquinimod group. This sample size also enables92% power to detect a statistically significant reduction of 30% in thetotal number of confirmed relapses between the laquinimod 0.6 mgtreatment group and the placebo group.

The analysis of the total numbers of confirmed relapses during thetreatment period is based on baseline adjusted Quasi-Likelihood(over-dispersed) Poisson Regression. The analysis of disability asassessed by MSFC at the end of the treatment period, and the analysis ofbrain atrophy as defined by the percent brain volume change frombaseline to the end of the treatment period is based on the baselineadjusted Analysis of Covariance. The analysis of the accumulation ofphysical disability measured by the time to a confirmed progression ofEDSS is based on Cox′ Proportional Hazard model.

Route and Dosage Form

Laquinimod Arm:

one capsule containing laquinimod 0.6 mg is administered orally oncedaily, preferably at the same hour every day with a glass of water.

The 0.6 mg laquinimod capsule is manufactured according to the methoddisclosed in PCT International Application Publication No.WO/2007/146248, published Dec. 21, 2007 (see, page 10, line 5 to page11, line 3).

Matching Placebo for Laquinimod Arm:

one capsule is administered orally once daily, preferably at the samehour every day with a glass of water.

Avonex® Arm:

one injection of Interferon β-1a (Avonex®) 30 mcg is administeredintramuscularly once weekly, preferably on the same day.

Outcome Measures

Primary Outcome Measure

The number of confirmed relapses during the treatment period.

Secondary Outcome Measures

Type-I error is controlled by employing the Hierarchical Approach, (i.e.each endpoint is analyzed only in case the preceding endpoint has ap-value less or equal to 0.05 for laquinimod 0.6 mg over placebocomparison) according to the following order:

-   1. Disability, as assessed by the MSFC score at the end of the    treatment period.-   2. Brain atrophy as defined by the percent brain volume change from    baseline at the end of the treatment period.-   3. Accumulation of physical disability measured by the time to    confirmed progression of EDSS (A confirmed progression of EDSS is    defined as a 1 point increase from baseline on EDSS score if    baseline was between 0 and 5.0, or a 0.5 point increase if baseline    EDSS was 5.5, confirmed 3 months later. Progression cannot be    confirmed during a relapse).    Safety and Tolerability Outcome Measures-   1. Adverse events.-   2. Vital signs.-   3. ECG findings.-   4. Clinical laboratory parameters.-   5. Proportion of subjects (%) who prematurely discontinued from the    study, reason of discontinuation and the time to withdrawal.-   6. Proportion of subjects (%) who prematurely discontinued from the    study due to AEs and the time to withdrawal.    Benefit/Risk Assessment

The Avonex® reference arm is compared to the placebo treatment groupwith respect to the same endpoints as for the comparison between thelaquinimod group and the placebo group.

These endpoints include:

-   1. The number of confirmed relapses during the treatment period.-   2. Disability measures based on EDSS and MSFC neurological scales.-   3. MRI parameters.-   4. Safety as assessed by adverse events, vital signs, ECG and    clinical laboratory parameters.-   5. Tolerability-   6. Quality of life scales such as: Modified Fatigue Impact Scale    (MFIS), General health status, as assessed by the EuroQoL (EQ5D)    questionnaire and the Short-Form general Health survey (SF-36)    subject-reported questionnaire.

The comparative assessment of the benefit/risk ratio between the twoactive arms (laquinimod and Avonex®) is based on the following aspects:

-   1. Efficacy parameters (Disability, MRI parameters, other    relapse-related endpoints).-   2. Safety and tolerability.-   3. Quality of life.    Additional Exploratory Endpoints

The following assessments are presented in an exploratory manner:

-   1. The total number of enhancing lesions on T1-weighted images taken    at months 12 and 24 (termination/early discontinuation).-   2. The number of enhancing lesions on a T1-weighted image taken at    month 12.-   3. The number of enhancing lesions on a T1-weighted image taken at    month 24 (termination/early discontinuation).-   4. The total number of new hypointense lesions (“black holes”) on    enhanced T1 scans taken at months 12 and 24 (termination/early    discontinuation).-   5. The total number of new hypointense lesions (“black holes”) on an    enhanced T1 scan taken at month 12.-   6. The total number of new hypointense lesions (“black holes”) on an    enhanced T1 scan taken at month 24 (termination/early    discontinuation).-   7. The total number of new/newly enlarging T2 lesions on scans taken    at months 12 and 24 (termination/early discontinuation).-   8. The number of new/newly enlarging T2 lesions on a scan taken at    month 12.-   9. The total number of new/newly enlarging T2 lesions on scans taken    at month 24 (termination/early discontinuation).-   10. The change in T2-lesion volume between months 0 (baseline) and    24 (termination/early discontinuation).-   11. The volume of T-2 lesions at termination/early discontinuation    of treatment period.-   12. The change from baseline to month 24 (termination/early    discontinuation) in the volume of hypointense lesions on enhanced T1    scans.-   13. Brain atrophy as defined by the percent brain volume change    from: 1) baseline to month 12 and b) month 12 to month 24    (termination/early discontinuation).-   14. The change from baseline to month 24 (termination/early    discontinuation) in binocular visual acuity, as assessed by the    number of letters read correctly from 2 meters distance on 1.25%,    2.5% and 100% contrast level Sloan letter/Tumbling-E charts.-   15. Subject-reported fatigue, as assessed by the Modified Fatigue    Impact Scale (MFIS).-   16. The time to the first confirmed relapse during the treatment    period.-   17. The proportion of relapse-free subjects.-   18. The rate of confirmed relapses during the treatment period    requiring hospitalization and/or IV steroids.-   19. The general health status, as assessed by the EuroQoL (EQ5D)    questionnaire.-   20. The general health status and health-related quality of life, as    assessed by the Short-Form general health survey (SF-36)    subject-reported questionnaire.    Assessment Methods

Neurostatus—A complete neurological assessment is performed at months −1(screening), 0 (baseline) and every 3 months thereafter untiltermination/early discontinuation of the study. The neurologicalassessment is a standardized neurological examination and assessment ofKurtzke's functional systems and expanded disability status.

The MS Functional Composite consists of 3 clinical examinations, theresults of which are combined using z-scores. The three clinicalexaminations include the PASAT, Timed 25 Foot walk and 9-Hole Peg Test.The PASAT and 9-Hole Peg tests are performed at months −1 (screening)(only for training purposes), 0 (baseline), 6, 12, 18 and 24(termination/early discontinuation) visits. The Timed 25 Foot walk testis performed each time the Neurostatus is performed.

The low-contrast visual acuity is assessed binocularly at months 0(baseline), 6, 12, 18 and 24 (termination/early discontinuation) visits,along with the MSFC assessments.

All subjects undergo 3 MRI scans (before and after gadoliniumadministration) at months: 0 (baseline), 12 and 24 (termination/earlydiscontinuation). The following parameters are assessed on each relevantscheduled scan:

Number of Gd-enhancing lesions on T1-weighted MRI scans, number ofnew/newly enlarging T₂ hyperintense lesions (with reference to theprevious scan), volume of T9 hyperintense lesions, number of newhypointense lesions on gadolinium-enhanced T₁-weighted MRI scans (‘blackholes’) (with reference to the previous scan), volume of hypointenselesions on gadolinium-enhanced T₁-weighted MRI scans, percent brainvolume change (with reference to previous scan), and normalized brainvolume (at baseline). All MRI data is evaluated and quantified by theMRI-AC.

Subject-reported fatigue assessed by the Modified Fatigue Impact Scale(MFIS) at months 0, 2, 6, 12, 18 and 24 (termination/earlydiscontinuation).

The general health status is assessed by the EuroQoL (EQ5D)questionnaire at months 0 (baseline) and 24 (termination/earlydiscontinuation).

The general health status is also assessed by the Short-Form generalhealth survey (SF-36) subject-reported questionnaire at month 0(baseline) and every 6 months thereafter, until termination/earlydiscontinuation. The SF-36 is a generic, self-administeredhealth-related quality of life instrument. In this study the instrumentis self-administrated during the visit.

Pharmacogenetic (PGt) assessment (ancillary study) is performed using an8.5 ml blood sample taken at baseline visit.

Economic Impact is assessed by the Work Productivity and ActivitiesImpairment (WPAIGH) Questionnaire (Ancillary Study, US sites only). TheWPAI-GH was developed for assessing productivity losses by measuring theeffect of general health and symptom severity on work as well as usualactivity productivity. This questionnaire is administered at month 0(baseline) and every 3 months thereafter, until month 24(termination/early discontinuation) visit. This assessment is performedin all subjects from US sites only.

Serum samples are collected from all subjects at months 0 (baseline), 12and 24 (termination/early discontinuation). They are collected forevaluation of immunological parameters and response to treatment witheither laquinimod or Avonex®, as well as for further investigation ofthe potential mechanism of action of laquinimod.

Vital signs (temperature, pulse and blood pressure) are measured at allscheduled and unscheduled visits. At baseline visit, blood pressure andpulse are measured 30 and 60 minutes after the first drugadministration. Blood pressure and pulse are recorded in a sittingposition after resting for 5 minutes.

Weight is measured at screening and month 24 (termination/earlydiscontinuation) visits. Height is measured at month −1 (screening)visit only.

ECGs are performed at months −1 (screening) (additional recording, up to30 minutes apart are performed if QTc is >450 msec according to themachine output), 0 (baseline), 1, 2, 3, 6, 12 18 and 24(termination/early discontinuation). At baseline visit, three ECGs areperformed at 15 minutes intervals to serve as integrated baseline ECG,by averaging baseline interval results for comparison to on-treatmentvalues.

The subject rests for at least 10 minutes before measurement is taken.Twelve-lead ECG is performed following the subject being in a supineposition for 5 minutes.

A physical examination is performed at months −1 (screening), 0(baseline) 1, 3, 6, 12, 18 and 24 (termination/early discontinuation).

A chest X-ray is performed at screening (month −1) if not performedwithin 6 months prior to screening and provided a report thereof can beobtained.

Results

Results from the BRAVO trial was reported in an Aug. 1, 2011 PressRelease from Teva Pharmaceutical Industries, Ltd., and in Vollmer et al.(Neurology, Apr. 24, 2012; 78 (Meeting Abstracts 1):S01.007), the entirecontents of each of which are hereby incorporated by reference into thisapplication.

Example 3 Post Hoc Analysis of ALLEGRO and BRAVO Trials: Evaluation ofLaquinimod Efficacy in Patient Subgroups

Introduction

Natural history data show that once EDSS of 3 is reached, disabilityprogression becomes both more likely and more rapid (Pittock et al.Neurology 2004; 62:51-9; Pittock et al. Neurology 2004; 62:601-6; Lerayet al. Brain 2010; 133:1900-1913). At EDSS>3, chronic diffuseinflammation may be a more important driver of disability.

Patients with an EDSS score of ≦3 are fully ambulatory; however gaitdysfunction is common in multiple sclerosis and is a key component ofdisability progression beyond this stage. Patients beyond this stageexperience growing motor impairment. Patients with an EDSS of 3.5 arefully ambulatory but already manifest moderate disability in selectedfunctional systems. Patients with an EDSS of 4 experience somerestriction in ambulation, but are up and about most of the day despiteclear neurological dysfunction. Subsequent EDSS progression ischaracterized by objective declines in ambulation and relatively severedisability in other functional domains.

RRMS patients who have demonstrated disease worsening (“worsening MS”)(Lublin, 2014) and reached an EDSS over 3 may experience confirmeddisability progression (CDP) more detrimental to daily function thanprogression from lower EDSS steps. The clinical need may be addressed bylaquinimod treatment, which significantly reduced annualized relapserate (ARR) and to a greater extent, CDP vs. placebo (PBO) in the phaseIII ALLEGRO and BRAVO studies. Laquinimod reduced EDSS-based CDP overalland in EDSS subgroups.

Summary

Nonclinical and clinical data support that laquinimod exerts a directprotective effect within the central nervous system, partly independentof its peripheral anti-inflammatory effects. The efficacy profile oforal Laquinimod (LAQ) 0.6 mg daily, demonstrated by ALLEGRO and BRAVOstudies described in Examples 1 and 2, respectively, differs from thatof other RRMS therapies. The observed effect of LAQ on ConfirmedDisability Progression (CDP) is disproportionately larger than would bepredicted by the observed LAQ effect on relapse rate reduction. Thisstudy investigates the effects of laquinimod 0.6 mg once-daily treatmenton individual Multiple Sclerosis Functional Composite (MSFC) componentsin the pooled ALLEGRO and BRAVO patient subgroups with baseline (BL)EDSS over 3, with aim to associate changes in T25FW and EDSS in thisworsening RRMS population at risk for progressive disease.

In pooled data from the Phase III ALLEGRO and BRAVO studies of orallaquinimod (LAQ) 0.6 mg once-daily (QD) vs. placebo (PBO) in RRMS, a 46%reduction in 6-month confirmed disability progression (CDP) (Vollmer,ECTRIMS 2011) was not accompanied by a significant treatment (Tx) effecton the Multiple Sclerosis Functional Composite (MSFC). However, for asubgroup of LAQ-treated patients with worsening MS (EDSS>3 at baseline[BL]), a 53% reduction in 6-month CDP was accompanied by a significantMSFC effect (mean z-score difference, 0.25) vs. PBO.

Methods

ALELGRO and BRAVO trials described above enrolled ambulatory patientswith RRMS, aged 18-55 years, with EDSS scores ≦5.5. Patients included inthe study had

-   -   1. ≧1 relapse in the previous year, or    -   2. 2 relapses in the previous 2 years, or    -   3. 1 relapse in the previous 1-2 years and ≧1 GdE lesion in the        previous year.

Patients were randomized 1:1 to LAQ 0.6 mg or PBO in the ALLEGRO study;in BRAVO patients were randomized 1:1:1 LAQ 0.6 or PBO or weeklyinterferon β 1a 30 μg.

Pooled data from ALLEGRO and BRAVO (Total N=1990; LAQ 0.6 mg QD N=984;PBO N=1006) trials were used in this post hoc analysis, in whichlaquinimod efficacy was evaluated in patient subgroups; in particularthe two patient subgroups: patients having baseline EDSS≦3, and patientshaving baseline EDSS>3. This post hoc analysis include patientsrandomized to LAQ 0.6 mg or PBO only. Endpoints include ARR, time to CDP(defined as an increase from baseline in EDSS score of ≧1 point ifbaseline EDSS is ≦5, or of ≧0.5 point if baseline EDSS is >5), sustainedfor 3 or 6 months; and MSFC components including the Timed 25-Foot Walk(T25FW) test.

LAQ vs. PBO treatment effects on change in MSFC subscores at 24 monthsfor the Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test(9HPT), and T25FW, in patients with EDSS>3 at baseline were assessed.Adjusted mean z-score differences and 95% CIs were evaluated by ANCOVA.

MRI endpoints included brain atrophy measured percent brain volumechange (PBVC), and cumulative numbers of gadolinium-enhancing (GdE) andnew T2 lesions at months 12 and 24.

Baseline statistics of the patients are shown in Table 5 below:

EDSS ≦ 3 (N = 1335) EDSS > 3 (N = 655) Pooled ALLEGRO Placebo LAQ 0.6Placebo LAQ 0.6 and BRAVO (n = 679) mg (n = 656) Total (n = 327) mg (n =328) Total Age (years), mean ± 36.5 ± 9.2  36.4 ± 9.1  36.5 ± 9.1  41.3± 8.5  ±41.3 ± 8.9 41.3 ± 8.7  SD Weight (kg) ± Mean 71.8 ± 15.8 70.2 ±16.0 70.1 ± 15.2 70.6 ± 16.1 SD BMI (kg/m²) ± Mean 24.9 ± 5.2  24.6 ±5.1  24.9 ± 49  24.8 ± 5.2  SD Female Gender, N 460 450 910 229 223 452(%) (67.7%) (68.6%) (68.2%) (70.0%) (68.0%) (69.0%) Previous MS 176 149325 72 91 163 treatment, N(%) (25.9%) (22.7%) (24.3%) (22.0%) (27.7%)(24.9%) EDSS at baseline, 2.0 ± 0.7 1.9 ± 0.7 1.9 ± 0.7 4.1 ± 0.7 4.1 ±0.6 4.1 ± 0.7 mean ± SD Time from MS 3.8 ± 4.8 3.6 ± 4.4 3.7 ± 4.6 4.8 ±5.0 5.6 ± 5.5 5.2 ± 5.3 diagnosis (years), mean ± SD Time from first 7.0± 6.2 6.8 ± 6.1 6.9 ± 6.1 9.7 ± 7.3 9.8 ± 7.0 9.7 ± 7.2 symptom (years),mean ± SD Number of Relapses 1.3 ± 0.7 1.2 ± 0.6 1.3 ± 0.7 1.3 ± 0.7 in1 year prior to screening (MEAN ± SD) Number of Relapses 1.8 ± 0.9 1.8 ±0.9 2.0 ± 1.0 2.0 ± 1.1 in 2 years prior to screening (MEAN ± SD) GdElesions > 0 at 271 267 133 126 Baseline, N (%) (39.9%) (40.7%) (40.7%)(38.4%) Number of GdE T1 1.4 ± 3.8 1.7 ± 4.5 1.5 ± 4.2 2.5 ± 8.3 1.9 ±4.6 2.2 ± 6.7 lesions, mean ± SD Volume of T2 lesions 7.5 ± 8.1 8.2 ±9.2 7.8 ± 8.7 11.8 ± 12.2 12.8 ± 11.8 12.3 ± 12.0 (cm³), mean ± SDBaseline brain 1609 ± 89.2   159 ± 90.8 1601 ± 90.0  1551 ± 90.5  1542 ±91.0  1547 ± 90.8  volume, mean ± SD

Overall, 655 patients (33%; LAQ n=328, PBO n=327) had baseline EDSS>3;mean (SD) baseline EDSS was 4.1 (0.7). One-fourth (24.9%) had receivedprior MS treatment. Compared with the EDSS≦3 subgroup, patients withbaseline EDSS>3 were older (mean age 41.3 vs. 36.5 years), had longerdisease duration (5.2 vs. 3.7 years), more GdE lesions, larger T2lesions, and lower brain volume (1547 vs. 1601 cm³) at baseline.

Results

Results from this post hoc analysis is shown in Table 6 below:

EDSS ≦3.0 EDSS >3.0 LAQ 0.6 mg, n = 656 LAQ 0.6 mg, (66.7%) n = 328(33.3%) PBO, n = 679 PBO, n = 327 (67.5%) (32.5%) Annualized RelapseRate Ratio [Cl] 0.80 0.75 [0.67; 0.95]; [0.60; 0.94]; p = 0.0103 p =0.0119 Time to 3-month CDP Hazard Ratio[Cl] 0.69 0.60 [0.50; 0.96];[0.38; 0.93]; p = 0.0256 p = 0.0229 Time to 6-month CDP Hazard Ratio[Cl]0.60 0.47 [0.41; 0.88]; [0.27; 0.82]; p = 0.0088 p = 0.0083 Disabilityas Assessed by MSFC z- Adjusted mean −0.02  0.25 Score at Month 24difference [Cl] [−0.12; 0.09];  [0.10; 0.39]; p = 0.7614 p = 0.0009Brain Atrophy as defined by PBVC Adjusted mean 0.34 0.39 difference [Cl][0.21; 0.47]; [0.21 0.58]; p < 0.0001 p < 0.0001 Cumulative GdE T1Lesions at Rate Ratio[Cl] 0.66 0.83 Months 12 and 24 [0.53; 0.82];[0.61; 1.13]; p = 0.0002 p = 0.2390 Cumulative New/Enlarging T2 RateRatio[Cl] 0.77 0.75 Lesions at Months 12 and 24 [0.65; 0.91]; [0.59;0.96]; p = 0.0024 p = 0.0214 T25FW Change from Baseline to Adj. MeanDiff.  0.055 −2.79  Month 24 Confidence Interval [−1.250; 1.359] [−4.664; −0.917] p-value  0.9342  0.0035 PASAT Change from Baseline toAdj. Mean Diff.  0.302  0.586 Month 24 Confidence Interval [−0.4670;1.071]  [−0.515; 1.687]  p-value  0.4411  0.2967 9HPT Change fromBaseline to Adj. Mean Diff. −1.108 −1.590 Month 24 Confidence Interval[−3.041; 0.681]  [−4.257; 1.077]  p-value  0.2137  0.2425

In the subgroup of RRMS patients with BL EDSS>3, LAQ significantlyreduced ARR (25%, p=0.012); 3-month CDP (40%, p=0.0083), 6-month CDP(53%, p=0.0009), and MSFC worsening (mean z-score difference of 0.25,p=0.0009). Improvement on the MSFC was driven by a 59% improvement withLAQ on the T25FW component vs. PBO in these patients. LAQ alsosignificantly reduced PBVC (adjusted mean Tx difference 0.39 [95% CI0.21, 0.58]; p<0.0001), and cumulative number of new T2 lesions (rateratio 0.75 [95% CI 0.59, 0.96]; p=0.021) vs PBO. LAQ treatment effect oncumulative number of GdE lesions was not statistically demonstrated inthis subgroup (rate ratio 0.83 [0.61, 1.13]; p=0.24).

MSFC Components

The difference between the results for Timed 25-Foot Walk (T25FW) testfor the two patient subgroups (EDSS≦3 and EDSS>3) is most pronounced.Among MSFC components, only the T25FW demonstrated a statisticallysignificant LAQ effect (p=0.0035) in the subgroup with BL EDSS>3. (SeeTable 6)

At baseline, subjects in the EDSS≦3 group completed the Timed 25-FootWalk in a mean (SD) of 5.40±5.3 seconds, and subjects in the EDSS>3group completed the T25FW in 8.29±6.81 seconds. A 59% LAQ Tx effect onmean [SE] T25FW time (−2.79 [0.96] seconds, 95% CI−4.66, −0.92;p=0.0035) appeared to drive the overall MSFC benefit in the EDSS>3subgroup as shown in FIG. 1. However, directional change consistent witha LAQ effect on the PASAT and 9HPT are present.

No treatment differences were seen in T25FW amongst subjects withEDSS≦3. In contrast, subjects with EDSS>3 who received placebo increasedtheir T25FW time by 4.7 seconds (adjusted mean, 95% CI 3.2-6.2) after 24months, while T25FW increase was 1.9 seconds (95% CI 0.5-3.4) insubjects treated with laquinimod (p=0.004; interaction p=0.01; effectsize=59%). Thus, the significant effect on ambulation appears unique tothe EDSS>3 subpopulation.

Association Between T25FW and EDSS Changes

An interaction between LAQ treatment effect on T25FW and CDP was found:there was a significant interaction (p<0.0001), whereby the T25FWtreatment effect was 8.6 seconds among subjects with EDSS>3 whoexperienced CDP.

Among patients who experienced 3-month CDP during the trial, the T25FWmarkedly increased from baseline to 24 months in the EDSS>3 subgroup(mean change [SD]=12.3 [±34.7] seconds, n=74). Patients in the EDSS≦3subgroup had little T25FW change, despite having CDP according to theEDSS (mean change [SD]=0.4 [±21.0] seconds, n=140). This finding isconsistent with the notion that EDSS progression beyond 3 is associatedwith ambulatory dysfunction.

There was little T25FW change among patients who did not experience CDP(mean change [SD]=0.90 [±9.3] seconds in the EDSS>3 group and 0.16 [5.9]seconds in the EDSS≦ subgroup).

A significant three-way subgroup×treatment×CDP interaction was found.That is, the LAQ treatment effect on the T25FW was accentuated inpatients with EDSS>3 who experienced CDP. PBO-treated patients whoexperienced CDP beyond an EDSS of 3 declined 8.6 seconds more thanequivalent LAQ-treated patients (FIG. 2).

T25FW data support the effect of laquinimod on CDP as an independent,relevant assessment in patients with EDSS greater than 3.

Conclusion

Laquinimod demonstrated significant benefits in relapse, disability, andMRI outcomes in patients with baseline EDSS>3.

A 53% reduction in 6-month CDP was observed in this worsening MSsubgroup, and its specific clinical meaningfulness is evidenced by a 59%T25FW ambulation benefit. These findings support the notion of animminent risk of disability progression marked by ambulatory decline inpatients who have reached an EDSS score above 3.

Laquinimod is associated with substantial benefit on ambulatoryfunction, producing clinically meaningful reductions in T25FW changeamongst those with baseline EDSS>3.

The treatment effect was heightened in those in this subgroup whoexperienced CDP.

REFERENCES

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What is claimed is:
 1. A method of reducing deterioration of ambulationof a human patient diagnosed to be afflicted with relapsing-remittingmultiple sclerosis (RRMS) and to have a baseline disability scoreaccording to the Kurtzke Expanded Disability Status Scale (EDSS) ofgreater than 3, comprising periodically administering to only thepatient diagnosed with RRMS and having a baseline EDSS score of greaterthan 3 an amount of laquinimod effective to reduce deterioration of thepatient's ambulation.
 2. The method of claim 1, wherein the amount oflaquinimod is effective to reduce the patient's relapse rate.
 3. Themethod of claim 1, wherein the amount of laquinimod is effective toreduce the patient's accumulation of physical disability.
 4. The methodof claim 1, wherein ambulation is assessed by the patient's Timed-25foot walk test score.
 5. The method of claim 1, wherein laquinimod isadministered orally and/or daily.
 6. The method of claim 1, whereinlaquinimod is administered at a daily dose of 0.3 mg laquinimod.
 7. Themethod of claim 1, wherein laquinimod is administered at a daily dose of0.6 mg laquinimod.
 8. The method of claim 1, wherein laquinimod isadministered as adjunct therapy with another RRMS treatment.
 9. Themethod of claim 8, wherein the other RRMS treatment is administration ofinterferon beta 1-a, interferon beta 1-b, glatiramer acetate,mitoxantrone or natalizumab.
 10. A method of reducing deterioration ofambulation of a human patient diagnosed to be afflicted with RRMS,worsening MS and to have a baseline disability score according to theKurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0,comprising periodically administering to only the patient diagnosed withRRMS, worsening MS and having an EDSS score of greater than 3.0 anamount of laquinimod effective to reduce deterioration of the patient'sambulation.
 11. The method of claim 10, wherein laquinimod isadministered orally and/or daily.
 12. The method of claim 10, whereinlaquinimod is administered at a daily dose of 0.3 mg laquinimod.
 13. Themethod of claim 10, wherein laquinimod is administered at a daily doseof 0.6 mg laquinimod.
 14. The method of claim 10, wherein laquinimod isadministered as adjunct therapy with another RRMS treatment.
 15. Themethod of claim 14, wherein the other RRMS treatment is administrationof interferon beta 1-a, interferon beta 1-b, glatiramer acetate,mitoxantrone or natalizumab.
 16. The method of claim 1, wherein thepatient has mobility impairment.
 17. The method of claim 1, wherein thepatient has a baseline EDSS score of 3.5-5.5.
 18. The method of claim 1,wherein the laquinimod is laquinimod sodium.
 19. The method of claim 16,wherein the mobility impairment is an ambulatory impairment.
 20. Themethod of claim 19, wherein the patient is not ambulatory.
 21. Themethod of claim 10, wherein the amount of laquinimod is effective toreduce the patient's relapse rate.
 22. The method of claim 10, whereinthe amount of laquinimod is effective to reduce the patient'saccumulation of physical disability.
 23. The method of claim 10, whereinambulation is assessed by the patient's Timed-25 foot walk test score.24. The method of claim 10, wherein the patient has a baseline EDSSscore of 3.5-5.5.
 25. The method of claim 10, wherein the laquinimod islaquinimod sodium.
 26. The method of claim 10, wherein the patient hasmobility impairment.
 27. The method of claim 26, wherein the mobilityimpairment is an ambulatory impairment.
 28. The method of claim 27,wherein the patient is not ambulatory.